Comparative Molecular Docking and ADMET Studies of Alpha-1-antitrypsin with Nanoparticles

Comparative Molecular Docking and ADMET Studies of Alpha-1-antitrypsin with Nanoparticles | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Molecular Docking and ADMET Studies of Alpha-1-antitrypsin with Nanoparticles Lakshmi M Sundeep, Sakthidasan Jayaprakash, Sandhya J, Mariamawit Milky This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4422570/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Stroke causes a large number of deaths yearly since it is not detected early. Stroke is caused by the narrowing of the blood vessels and reducing the flow of blood and oxygen to the brain. When ischemic stroke is about to occur some proteins are expressed making them a potential biomarker. The biomarker we chose to work with is alpha-1-antitrypsin because there are studies showing the correlation of alpha-1-antitrypsin with the acute stage of stroke. Due to the inflammation caused during stroke, there will be a rise in alpha-1-antitrypsin. By docking alpha-1-antitrypsin with nanoparticles we can use them as a diagnostic tool for stroke. Nanoparticles have shown a promising result in detection of cancer, arthritis and other infectious disease making it a potential ligand. From this study titanium oxide showed the lowest binding energy and showed lower toxicity compared to the other nanoparticles used in the study. By performing further studies, binding of alpha-1-antitrypsin and titanium oxide can be used for the detection of stroke at the early stage. Nanoparticles Alpha-1-antitrypsin Stroke Molecular docking ADMET Nanotechnology Biomarkers Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 1) INTRODUCTION A stroke is a neurological condition that is clinically described as an immediate, focal loss of function in the brain that is caused by vascular injury to the central nervous system (Murphy, S et al. 2020). Stroke can be divided into three namely ischemic stroke ,hemorrhagic stroke and subarachnoid hemorrhage. Blockages in blood vessels that restrict the flow of oxygenated blood to the brain cause ischemic strokes (Chugh C. et al. 2019).The depletion of oxygen can be due to the clogging of arteries, blockage of blood vessels or rupturing of arteries (Kuriakose D et al. 2020). Stroke contributes to a large number of deaths each year. In 2016, 5.5 million deaths were recorded due to stroke(GBD 2016 Stroke Collaborators et al. 2019). Out of the three types of strokes, ischemic stroke is common accounting 87% of stroke cases in the United States of America (Barthels D. et al. 2020). However, the early diagnosis and treatment for ischemic stroke is limited. 1.1) Biomarkers for Ischemic Stroke The majority of research on biomarkers for ischemic stroke has focused on single proteins chosen for their established connections to the pathophysiology of ischemic stroke. These comprise markers of endothelium, coagulation/thrombosis, inflammation, and brain tissue damage (Jickling et al. 2011) . For this paper, we will be focusing on alpha-1-antitrypsin as a biomarker for stroke. Alpha1-antitrypsin (AAT) is a serine protease inhibitor that plays a crucial role in protecting tissues from damage caused by excessive proteolytic activity. Recent studies have suggested that AAT can serve as a potential biomarker for stroke patients due to its involvement in the inflammatory response and tissue repair mechanisms following cerebral ischemia.studies have suggested that alpha1-antitrypsin (AAT) can be used as a biomarker for stroke patients (Misra S. et al. 2022). Elevated levels of AAT have been observed in stroke patients compared to healthy controls, and AAT's involvement in inflammation and tissue repair processes further supports its potential as a biomarker (Mahta et al. 2020). 1.2) Nanotechnology Metal nanοparticles have been used in different applications. They can impressively change biological and physicochemical characteristics as they have high electrical prοperties, increased tolerance to mechanical and thermal pressure, high surface area, and high οptical and magnetic prοperties (Xue Z. et al. 2019) . 1.2.1) Silver Based Nanoparticles Silver nanoparticles have been always considered as the promising nanoparticle for the early diagnosis and detection mechanisms in the optical biosensors (Velusamy P. et al. 2016). Different physical and chemical approaches have been used to stabilize silver nanoparticles are used in different sensors such as, enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, Raman spectroscopy, and electrochemical biosensor to detection different biomarkers at greater sensitivity This is possible because when a biomolecule is attached to Ag NPs, it exhibits an increase in local refractive index and an Ag extinction shift ( Iravani S. et al. 2014 ). 1.2.2) Titanium Based Nanoparticles Titanium dioxide (TiO2) is a semiconductor NP that is broadly employed in diagnostic and therapeutic uses according to its non-toxicity (Yin Z. et al. 2013). TiO2 nanoparticles have been extensively explored for biosensing applications due to their high surface area and excellent biocompatibility. ( Wang et al. 2019 ) developed a TiO2 NP-based electrochemical biosensor for the detection of cancer biomarkers. The study reported high sensitivity and selectivity, indicating the potential of TiO2 nanoparticles in early cancer diagnosis. Numerous studies have highlighted the use of TiO2 nanoparticles in optical imaging techniques such as fluorescence imaging. One scenario is the use of TiO2 nanoparticles as fluorescent probes for cancer cell imaging. The enhanced fluorescence emission and improved cellular uptake of TiO2 nanoparticle makes it a promising tool for cancer diagnosis. (Smitha et al. 2018 ). 1.2.3) Zinc Based Nanoparticles Zinc oxide (ZnO) is well known for its high isoelectric content, biocompatibility, and other multifunctional qualities, making it an excellent transduction material for the development of biological sensors. ZnO's appealing qualities improve sensory capabilities and help preserve the biological activity of immobilised biomolecules. By enhancing sensitivity and selectivity, the large surface area of the ZnO nanostructure allows for signal amplification in the detection of target biomarkers. ZnO provides a unique matrix for the immobilisation of biomolecules since its isoelectric point (IEP) of 9.5 is higher than that of the majority of biomolecules (Jouyandeh M. et al. 2022). 1.2.4) Copper Based Nanoparticles Copper is a noble metal alternative because of its notable benefits such as low cost, non-toxicity, and strong electrochemical activity. Copper has shown potential as contrast agents for biomedical imaging techniques like MRI and optical imaging. The unique magnetic and optical properties of copper enable enhanced imaging resolution and sensitivity, facilitating the diagnosis and monitoring of diseases ( Rabiee, N. et al. 2020 ). Copper-based nanomaterials, such as copper nanoparticles and copper-based quantum dots, have shown promise in optical biosensing. These nanomaterials exhibit excellent light absorption and emission properties, allowing for sensitive detection of biomolecular interactions and disease markers. 1.3 Importance of The Study The use of molecular docking techniques will allow us to investigate the interaction between alpha-1-antitrypsin and various biocompatible nanoparticles. This research is significant because it explores the potential for developing non-invasive diagnostic tools for early-stage ischemic stroke patients. By studying the docking of alpha-1-antitrypsin with nanoparticles such as titanium oxide, silver oxide, copper oxide, and zinc oxide, we can gain insights into the binding affinity and stability of these interactions. This information can help determine the use of these nanoparticles as carriers or sensors for alpha-1-antitrypsin in diagnostic applications. If successful, this research could lead to the development of novel diagnostic tools that can detect elevated levels of alpha-1-antitrypsin in stroke patients. Early detection of stroke is crucial for timely intervention and treatment, as it can significantly improve patient outcomes. Non-invasive diagnostic tools based on the molecular docking of alpha-1-antitrypsin with biocompatible nanoparticles could provide a convenient and efficient method for early-stage stroke diagnosis. 2) Materials and Methods 2.1) Tools and Softwares The protein structure was obtained using PDB while the ligands were retrieved from ChemSpider. The chemical format of the nanoparticles were converted to the AutoDock format(.pdbqt) using OpenBabel. Autodock 4.2 was used for docking and analyzing purposes. SwissADMET web version ( http://www.swissadme.ch ) was used to do the ADMET studies. 2.2) Molecular Docking Experiment 2.2.1) Protein Preparation Alpha-1-antitrypsin (1HP7) was retrieved from PDB. The retrieved protein was open in Autodock 4.2. The preparation of the protein will include numerous stages in order to optimize the structure for proper docking. The initial step is the removal of water molecules followed by removal of unnecessary chains. For our protein, alpha-1-antitrypsin, we removed all the chains except chain A. The ligands from chain A, Beta mercaptoethanol and zinc, were removed. Finally polar hydrogens were added to the chain and Gasteiger Charge was computed. The final structure was saved in .pdb format. 2.2.2) Ligand Preparation The nanoparticles that were chosen for the molecular docking process were titanium oxide, silver oxide, iron oxide and zinc oxide.The structures of the given nanoparticles were retrieved from ChemSpider.They were retrieved in .Mol format which were converted to .pdbqt using the tool open babel. The .pdbqt file was opened in Autodock 4.2 as a ligand. 2.2.3) Preparing Grid Map Set the target protein. Grid->Macromolecule->Choose. Select protein.pdb. Set the ligand. Grid-> Set Map Types-> Choose. Select ligand.pdbqt. Set the grid box position and size and save the grid positioning. Save the grid file in .gpf format. 2.2.4) Setup Docking Parameter Set the target protein. Docking->Macromolecule->Set file name. Select protein.pdbqs. Set the ligand. Docking-> Ligand-> Choose. Select ligand.pdbqt. The search and the docking parameters are set. They were set as the default value. Set the docking parameter file. Docking-> Output-> Lamarckian Save the file in .dpf format 2.2.4) Run the AutoGrid and AutoDock Run the autogrid and autodock by choosing the .gpf and .dpf files respectively. Before running choose the destination file and add all the necessary. The docking results will be displayed on the command prompt. The outputs will be further analyzed with other softwares. 2.3) ADMET Studies The evaluation of a drug's pharmacokinetics, or absorption, distribution, metabolism, excretion, and toxicity, is known as an ADMET study. Predicting a drug's destiny and the effects it will have on the body, including how much of it will be absorbed as taken orally and how much will pass through the digestive system ( Flores-Holguín et al. 2021 ). ADMET profiles were analyzed using an online version of SwissADME web tool ( http://www.swissadme.ch)(Daina A et al. 2017) . The Simplified Molecular Input Line Entry System (SMILES) formats of all the ligands were obtained by converting the (.mol format) using OpenBabel. The predicted properties was compared among the ligands. 3) Result and Discussion 3.1) Docking Results The alpha-1-antitrypsin (PDB ID 1HP7) from PDB and the nanoparticles retrieved from ChemSpider are shown in Fig. 2 and Fig. 3 respectively. The Parameter set for the Grid Box (Fig. 4 ) was based on the concept of blind docking.We allowed the Grid Box to cover the entire protein as shown in Fig. 4 so that the docking can happen throughout the protein instead of restricting it to a specific region. 3.1.1) Zinc Oxide and Alpha-1-antitrypsin Interaction For the molecular docking of alpha-1-antitrypsin and zinc oxide the minimum binding energy was − 2.58 . During the interaction between alpha-1-antitrypsin and zinc oxide, a hydrogen bond was formed with VAL311 of the alpha-1-antitrypsin. 3.1.2) Silver Oxide and Alpha-1-antitrypsin Interaction For the molecular docking of alpha-1-antitrypsin and silver oxide the minimum binding energy was − 1.91 . LEU318 and LEU327 bounded with the silver oxide using hydrogen bonding. 3.1.3) Titanium Oxide and Alpha-1-antitrypsin Interaction The titanium oxide interacts with GLY192, TYR244, THR339 and ASP341. The bond between glycine, aspartic acid and titanium oxide is hydrogen bond. Out of the ten runs number seven shows the minimum binding energy with a value of -3.07 kcal/mol . Run six and one were ranked second and third respectively with a binding energy close to -3.07. 3.1.4) Copper Oxide and Alpha-1-antitrypsin Interaction For the molecular docking of alpha-1-antitrypsin and copper oxide the minimum binding energy was − 1.72. The interaction between copper oxide and alpha-1-antitrypsin is due to the hydrogen bonding between the copper oxide and LEU318 and LEU327. 3.2) Binding Energy Comparison The ideal nanoparticle will be the one having the minimum binding energy with alpha-1-antitrypsin. Table 1 Minimum Binding Energy of Each Nanoparticle Nanoparticle Minimum Binding Energy Rank Zinc Oxide -2.58 Second Silver Oxide -1.91 Third Titanium Oxide -3.07 First Copper Oxide -1.72 Fourth From the table above (Table 1 ) it is observed that titanium oxide is the ideal nanoparticle to be used for the molecular docking of alpha-1-antitrypsin with a minimum binding energy of -3.07 and copper oxide is the least favorable nanoparticle as it has a minimum binding energy of -1.72. 3.3) ADMET Profiles of the Ligands Table 2: Selected in-silico ADMET properties of the ligands ADMET predicted profile classificat ions Human Intestinal Absorptio n Titanium Zinc Oxide Oxide Silver Oxide Copper Oxide Value Probabil ity Value Probabil ity Value Probabil ity Value Probabil ity + 0.9619 + 0.9769 + 0.9769 + 0.9769 Blood Brain Barrier + 0.9750 + 0.9750 + 0.9750 + 0.9750 Human oral bioavailab ility + 0.7857 + 0.7571 + 0.8143 + 0.8143 Hepatotox icity + 0.9000 + 0.9250 + 0.925 + 0.9125 Respirator y toxicity - 0.7556 - 0.8444 - 0.8444 - 0.8444 Reproduct ive toxicity - 0.8111 - 0.7000 - 0.7000 - 0.7000 Mitochond rial toxicity - 0.5500 - 0.7375 - 0.7375 - 0.7375 Nephrotox icity + 0.8215 + 0.7375 + 0.7316 + 0.7316 Biodegrad ation + 0.6750 + 0.6500 + 0.6500 + 0.6500 Table 3 Physicochemical predictions of the ligands Property Value for Titanium Oxide Value for Zinc Oxide Value for Silver Oxide Value for Copper Oxide Molecular Weight 79.86 81.39 123.87 79.55 AlogP -0.24 -0.12 -0.12 -0.12 H-Bond Acceptor 2 1 1 1 H-Bond Donor 0 0 0 0 Rotatable bond 0 0 0 0 Applicability Domain In Domain In Domain In Domain In Domain The parameters linked with the blood-brain barrier, human intestinal absorption (HIA) and other toxicity tests were examined in order to analyze the absorption of ligands (nanoparticles). The values for the given nanoparticles were approximately in same range with less value variation. The blood-brain barrier (BBB) was examined in relation to medication distribution ( Pujari et al. 2021 ). Because the blood-brain barrier tells us whether or not the nanoparticles will cross the brain barrier, it is crucial. The value for blood-brain barrier for all the nanoparticles is 0.9750. This shows that the nanoparticles can easily pass through the blood brain barrier and bind bind with alpha-1-antitrypsin. The human intestinal absorption value for the ligands falls in the acceptable range which is 0.5-1. The ligands within the acceptable range can easily pass from the intestine to the blood stream. Human intestinal absorption is an essential to determine whether the drug will reach its target (Yan A et al. 2008 ). 4) Conclusion Early detection of stroke can be possible by using the proteins expressed in blood as a biomarker. Alpha-1-antitrypsin is one of the proteins expressed as a result of inflammation caused by the depletion of oxygen in the brain. In this study, computational docking was performed to show the interaction of alpha-1-antitrypsin with four ligands which are namely zinc oxide, titanium oxide, copper oxide and silver oxide. Compared to the other nanoparticles titanium oxide exhibited a low binding energy of -3.07 kcal/mol. ADMET studies were also done to find the toxicity levels of the ligands. One of the essential results of the ADMET studies was the blood brain barrier value. Blood brain barrier(BBB) is a semipermeable membrane which plays a major role in the movement of ions and molecules between the blood and brain. The BBB value for all the ligands was high meaning that the nanoparticles can easily pass through the brain and bind with alpha-1-antitrypsin at the site of inflammation. The results from the molecular docking and the ADMET studies shows that titanium oxide is comparatively the best ligand to bind with alpha-1-antitrypsin. Our future studies will include an in vitro study on the binding of alpha-1-antitrypsin and titanium oxide nanoparticles. This study will open new windows in healthcare centers by introducing a non-invasive method of detecting stroke during the early stage. Declarations Author Contribution 1. Ms. Lakshmi Sundeep developed the proof of concept2. Mariamawit wrote the main manuscript text3. Dr. J.Saktidasan prepared all the figures4. All authors reviewed the manuscript5. Dr. J Sandhya developed the tables References Barthels D, Das H (2020) Current advances in ischemic stroke research and therapies. Biochim et Biophys acta Mol basis disease 1866(4):165260. https://doi.org/10.1016/j.bbadis.2018.09.012 Chugh C (2019) Acute Ischemic Stroke: Management Approach. 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PLoS One, 11(6), e0157612 Wang J, Zhu G, You M, Song E, Shukoor MI (2019) A TiO2 nanoparticle-based electrochemical biosensor for the detection of cancer biomarkers. Sensors and Actuators B: Chemical, 297 Xue Z., Zhang, Y., Yu, W., Zhang, J., Wang, J., Wan, F., … Kou, X. (2019). Recent advances in aflatoxin B1 detection based on nanotechnology and nanomaterials-A review.Analytica chimica acta, 1069, 1–27 Yan A, Wang Z, Cai Z (2008) Prediction of human intestinal absorption by GA feature selection and support vector machine regression. Int J Mol Sci 9(10):1961–1976. https://doi.org/10.3390/ijms9101961 Yin ZF, Wu L, Yang HG, Su YH (2013) Recent progress in biomedical applications of titanium dioxide. Phys Chem Chem Phys 15(14):4844–4858 Additional Declarations No competing interests reported. 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Parameters\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/0dcc0917855ffee3b9e6300b.png"},{"id":57185661,"identity":"9b457caa-6322-4515-9d62-abb1da4c4800","added_by":"auto","created_at":"2024-05-27 05:46:19","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":87017,"visible":true,"origin":"","legend":"\u003cp\u003eClustering Histogram for Zinc Oxide\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/f822e940c07ea3db7d6d9535.png"},{"id":57185153,"identity":"80e866c6-016d-4e68-b2db-a11ed69aa249","added_by":"auto","created_at":"2024-05-27 05:38:19","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":378095,"visible":true,"origin":"","legend":"\u003cp\u003eInteraction of alpha-1-antitrypsin and zinc oxide\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/40d56470788b29284ab3680b.png"},{"id":57185155,"identity":"5e38da87-03c3-401a-8852-4c42ef583f3b","added_by":"auto","created_at":"2024-05-27 05:38:19","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":82414,"visible":true,"origin":"","legend":"\u003cp\u003eClustering Histogram for Silver Oxide\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/d6d7210701e9fb4df92da879.png"},{"id":57185663,"identity":"851dca64-a53b-47f4-9b3d-7aac430dee73","added_by":"auto","created_at":"2024-05-27 05:46:19","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":296535,"visible":true,"origin":"","legend":"\u003cp\u003eInteraction of alpha-1-antitrypsin and silver oxide\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/eddd922ad2d9b21988501194.png"},{"id":57185156,"identity":"2521bf1c-31eb-4092-8654-0194e1b30275","added_by":"auto","created_at":"2024-05-27 05:38:19","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":73937,"visible":true,"origin":"","legend":"\u003cp\u003eClustering Histogram from Titanium Oxide\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/c4fbdc96a1db0e35329c3267.png"},{"id":57185158,"identity":"fe8152eb-2158-4b60-ae78-2a96fab09ff7","added_by":"auto","created_at":"2024-05-27 05:38:19","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":266562,"visible":true,"origin":"","legend":"\u003cp\u003eBinding of Titanium oxide and alpha-1-antitrypsin\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/b1997ec70bf8fbb1c61c5bb7.png"},{"id":57185157,"identity":"9d2e8471-c3e1-4b8e-b22d-2d0b47a859bc","added_by":"auto","created_at":"2024-05-27 05:38:19","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":63761,"visible":true,"origin":"","legend":"\u003cp\u003eClustering Histogram for Copper Oxide\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/76eaf732a157358713a1f323.png"},{"id":57185159,"identity":"3fc5d374-27d0-4099-90f5-1fe2eef31479","added_by":"auto","created_at":"2024-05-27 05:38:19","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":265093,"visible":true,"origin":"","legend":"\u003cp\u003eInteraction of alpha-1-antitrypsin and copper oxide\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/6c26046b62e6adf3bf5a9c89.png"},{"id":58903306,"identity":"3c505da0-6bda-477f-a1fa-f3f44a0b5ff3","added_by":"auto","created_at":"2024-06-24 02:07:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3033452,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4422570/v1/6c6edfbb-8f03-4ec4-b873-8b6cab9edbe4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative Molecular Docking and ADMET Studies of Alpha-1-antitrypsin with Nanoparticles","fulltext":[{"header":"1) INTRODUCTION","content":"\u003cp\u003eA stroke is a neurological condition that is clinically described as an immediate, focal loss of function in the brain that is caused by vascular injury to the central nervous system (Murphy, S et al. 2020). Stroke can be divided into three namely ischemic stroke ,hemorrhagic stroke and subarachnoid hemorrhage. Blockages in blood vessels that restrict the flow of oxygenated blood to the brain cause ischemic strokes (Chugh C. et al. 2019).The depletion of oxygen can be due to the clogging of arteries, blockage of blood vessels or rupturing of arteries (Kuriakose D et al. 2020). Stroke contributes to a large number of deaths each year. In 2016, 5.5\u0026nbsp;million deaths were recorded due to stroke(GBD 2016 Stroke Collaborators et al. 2019). Out of the three types of strokes, ischemic stroke is common accounting 87% of stroke cases in the United States of America (Barthels D. et al. 2020). However, the early diagnosis and treatment for ischemic stroke is limited.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.1) Biomarkers for Ischemic Stroke\u003c/h2\u003e \u003cp\u003eThe majority of research on biomarkers for ischemic stroke has focused on single proteins chosen for their established connections to the pathophysiology of ischemic stroke. These comprise markers of endothelium, coagulation/thrombosis, inflammation, and brain tissue damage \u003cem\u003e(Jickling et al. 2011)\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eFor this paper, we will be focusing on alpha-1-antitrypsin as a biomarker for stroke. Alpha1-antitrypsin (AAT) is a serine protease inhibitor that plays a crucial role in protecting tissues from damage caused by excessive proteolytic activity. Recent studies have suggested that AAT can serve as a potential biomarker for stroke patients due to its involvement in the inflammatory response and tissue repair mechanisms following cerebral ischemia.studies have suggested that alpha1-antitrypsin (AAT) can be used as a biomarker for stroke patients \u003cem\u003e(Misra S. et al. 2022).\u003c/em\u003e Elevated levels of AAT have been observed in stroke patients compared to healthy controls, and AAT's involvement in inflammation and tissue repair processes further supports its potential as a biomarker \u003cem\u003e(Mahta et al. 2020).\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.2) Nanotechnology\u003c/h2\u003e \u003cp\u003eMetal nanοparticles have been used in different applications. They can impressively change biological and physicochemical characteristics as they have high electrical prοperties, increased tolerance to mechanical and thermal pressure, high surface area, and high οptical and magnetic prοperties \u003cem\u003e(Xue Z. et al. 2019)\u003c/em\u003e.\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003e1.2.1) Silver Based Nanoparticles\u003c/h2\u003e \u003cp\u003eSilver nanoparticles have been always considered as the promising nanoparticle for the early diagnosis and detection mechanisms in the optical biosensors \u003cem\u003e(Velusamy P. et al. 2016).\u003c/em\u003e Different physical and chemical approaches have been used to stabilize silver nanoparticles are used in different sensors such as, enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, Raman spectroscopy, and electrochemical biosensor to detection different biomarkers at greater sensitivity This is possible because when a biomolecule is attached to Ag NPs, it exhibits an increase in local refractive index and an Ag extinction shift \u003cem\u003e(\u003c/em\u003eIravani S. et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e1.2.2) Titanium Based Nanoparticles\u003c/h2\u003e \u003cp\u003eTitanium dioxide (TiO2) is a semiconductor NP that is broadly employed in diagnostic and therapeutic uses according to its non-toxicity \u003cem\u003e(Yin Z. et al. 2013).\u003c/em\u003e TiO2 nanoparticles have been extensively explored for biosensing applications due to their high surface area and excellent biocompatibility. \u003cem\u003e(\u003c/em\u003eWang et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) developed a TiO2 NP-based electrochemical biosensor for the detection of cancer biomarkers. The study reported high sensitivity and selectivity, indicating the potential of TiO2 nanoparticles in early cancer diagnosis.\u003c/p\u003e \u003cp\u003eNumerous studies have highlighted the use of TiO2 nanoparticles in optical imaging techniques such as fluorescence imaging. One scenario is the use of TiO2 nanoparticles as fluorescent probes for cancer cell imaging. The enhanced fluorescence emission and improved cellular uptake of TiO2 nanoparticle makes it a promising tool for cancer diagnosis. (Smitha et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e1.2.3) Zinc Based Nanoparticles\u003c/h2\u003e \u003cp\u003eZinc oxide (ZnO) is well known for its high isoelectric content, biocompatibility, and other multifunctional qualities, making it an excellent transduction material for the development of biological sensors. ZnO's appealing qualities improve sensory capabilities and help preserve the biological activity of immobilised biomolecules. By enhancing sensitivity and selectivity, the large surface area of the ZnO nanostructure allows for signal amplification in the detection of target biomarkers. ZnO provides a unique matrix for the immobilisation of biomolecules since its isoelectric point (IEP) of 9.5 is higher than that of the majority of biomolecules (Jouyandeh M. et al. 2022).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e1.2.4) Copper Based Nanoparticles\u003c/h2\u003e \u003cp\u003eCopper is a noble metal alternative because of its notable benefits such as low cost, non-toxicity, and strong electrochemical activity. Copper has shown potential as contrast agents for biomedical imaging techniques like MRI and optical imaging. The unique magnetic and optical properties of copper enable enhanced imaging resolution and sensitivity, facilitating the diagnosis and monitoring of diseases \u003cem\u003e(\u003c/em\u003eRabiee, N. et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCopper-based nanomaterials, such as copper nanoparticles and copper-based quantum dots, have shown promise in optical biosensing. These nanomaterials exhibit excellent light absorption and emission properties, allowing for sensitive detection of biomolecular interactions and disease markers.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e1.3 Importance of The Study\u003c/h2\u003e \u003cp\u003eThe use of molecular docking techniques will allow us to investigate the interaction between alpha-1-antitrypsin and various biocompatible nanoparticles. This research is significant because it explores the potential for developing non-invasive diagnostic tools for early-stage ischemic stroke patients.\u003c/p\u003e \u003cp\u003eBy studying the docking of alpha-1-antitrypsin with nanoparticles such as titanium oxide, silver oxide, copper oxide, and zinc oxide, we can gain insights into the binding affinity and stability of these interactions. This information can help determine the use of these nanoparticles as carriers or sensors for alpha-1-antitrypsin in diagnostic applications.\u003c/p\u003e \u003cp\u003eIf successful, this research could lead to the development of novel diagnostic tools that can detect elevated levels of alpha-1-antitrypsin in stroke patients. Early detection of stroke is crucial for timely intervention and treatment, as it can significantly improve patient outcomes. Non-invasive diagnostic tools based on the molecular docking of alpha-1-antitrypsin with biocompatible nanoparticles could provide a convenient and efficient method for early-stage stroke diagnosis.\u003c/p\u003e \u003c/div\u003e"},{"header":"2) Materials and Methods","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.1) Tools and Softwares\u003c/h2\u003e \u003cp\u003eThe protein structure was obtained using PDB while the ligands were retrieved from ChemSpider. The chemical format of the nanoparticles were converted to the AutoDock format(.pdbqt) using OpenBabel. Autodock 4.2 was used for docking and analyzing purposes. SwissADMET web version (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.swissadme.ch\u003c/span\u003e\u003cspan address=\"http://www.swissadme.ch\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e)\u003c/span\u003e was used to do the ADMET studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.2) Molecular Docking Experiment\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e2.2.1) Protein Preparation\u003c/h2\u003e \u003cp\u003eAlpha-1-antitrypsin (1HP7) was retrieved from PDB. The retrieved protein was open in Autodock 4.2. The preparation of the protein will include numerous stages in order to optimize the structure for proper docking. The initial step is the removal of water molecules followed by removal of unnecessary chains. For our protein, alpha-1-antitrypsin, we removed all the chains except chain A. The ligands from chain A, Beta mercaptoethanol and zinc, were removed. Finally polar hydrogens were added to the chain and Gasteiger Charge was computed. The final structure was saved in .pdb format.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e2.2.2) Ligand Preparation\u003c/h2\u003e \u003cp\u003eThe nanoparticles that were chosen for the molecular docking process were titanium oxide, silver oxide, iron oxide and zinc oxide.The structures of the given nanoparticles were retrieved from ChemSpider.They were retrieved in .Mol format which were converted to .pdbqt using the tool open babel. The .pdbqt file was opened in Autodock 4.2 as a ligand.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e2.2.3) Preparing Grid Map\u003c/h2\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSet the target protein. Grid-\u0026gt;Macromolecule-\u0026gt;Choose. Select protein.pdb.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSet the ligand. Grid-\u0026gt; Set Map Types-\u0026gt; Choose. Select ligand.pdbqt.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSet the grid box position and size and save the grid positioning.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSave the grid file in .gpf format.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e2.2.4) Setup Docking Parameter\u003c/h2\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSet the target protein. Docking-\u0026gt;Macromolecule-\u0026gt;Set file name. Select protein.pdbqs.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSet the ligand. Docking-\u0026gt; Ligand-\u0026gt; Choose. Select ligand.pdbqt.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe search and the docking parameters are set. They were set as the default value.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSet the docking parameter file. Docking-\u0026gt; Output-\u0026gt; Lamarckian\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSave the file in .dpf format\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e2.2.4) Run the AutoGrid and AutoDock\u003c/h2\u003e \u003cp\u003eRun the autogrid and autodock by choosing the .gpf and .dpf files respectively. Before running choose the destination file and add all the necessary. The docking results will be displayed on the command prompt. The outputs will be further analyzed with other softwares.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e2.3) ADMET Studies\u003c/h2\u003e \u003cp\u003eThe evaluation of a drug's pharmacokinetics, or absorption, distribution, metabolism, excretion, and toxicity, is known as an ADMET study. Predicting a drug's destiny and the effects it will have on the body, including how much of it will be absorbed as taken orally and how much will pass through the digestive system \u003cem\u003e(\u003c/em\u003eFlores-Holgu\u0026iacute;n et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). ADMET profiles were analyzed using an online version of SwissADME web tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.swissadme.ch)(Daina A et al. 2017)\u003c/span\u003e\u003cspan address=\"http://www.swissadme.ch)(Daina A et al. 2017)\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. The Simplified Molecular Input Line Entry System (SMILES) formats of all the ligands were obtained by converting the (.mol format) using OpenBabel. The predicted properties was compared among the ligands.\u003c/p\u003e \u003c/div\u003e"},{"header":"3) Result and Discussion","content":"\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1) Docking Results\u003c/h2\u003e\n \u003cp\u003eThe alpha-1-antitrypsin (PDB ID 1HP7) from PDB and the nanoparticles retrieved from ChemSpider are shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e respectively.\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003eThe Parameter set for the Grid Box (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e) was based on the concept of blind docking.We allowed the Grid Box to cover the entire protein as shown in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e so that the docking can happen throughout the protein instead of restricting it to a specific region.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e\n \u003ch2\u003e3.1.1) Zinc Oxide and Alpha-1-antitrypsin Interaction\u003c/h2\u003e\n \u003cp\u003eFor the molecular docking of alpha-1-antitrypsin and zinc oxide the \u003cstrong\u003eminimum binding energy\u003c/strong\u003e was \u003cstrong\u003e\u0026minus;\u0026thinsp;2.58\u003c/strong\u003e. During the interaction between alpha-1-antitrypsin and zinc oxide, a hydrogen bond was formed with VAL311 of the alpha-1-antitrypsin.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e\n \u003ch2\u003e3.1.2) Silver Oxide and Alpha-1-antitrypsin Interaction\u003c/h2\u003e\n \u003cp\u003eFor the molecular docking of alpha-1-antitrypsin and silver oxide the \u003cstrong\u003eminimum binding energy was \u003cstrong\u003e\u0026minus;\u0026thinsp;1.91\u003c/strong\u003e. LEU318 and LEU327 bounded with the silver oxide using hydrogen bonding.\u003c/strong\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec22\" class=\"Section3\"\u003e\n \u003ch2\u003e3.1.3) Titanium Oxide and Alpha-1-antitrypsin Interaction\u003c/h2\u003e\n \u003cp\u003eThe titanium oxide interacts with GLY192, TYR244, THR339 and ASP341. The bond between glycine, aspartic acid and titanium oxide is hydrogen bond. Out of the ten runs number seven shows the \u003cstrong\u003eminimum binding energy\u003c/strong\u003e with a value of \u003cstrong\u003e-3.07 kcal/mol\u003c/strong\u003e. Run six and one were ranked second and third respectively with a binding energy close to -3.07.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n \u003ch2\u003e3.1.4) Copper Oxide and Alpha-1-antitrypsin Interaction\u003c/h2\u003e\n \u003cp\u003eFor the molecular docking of alpha-1-antitrypsin and copper oxide the \u003cstrong\u003eminimum binding energy\u003c/strong\u003e was \u003cstrong\u003e\u0026minus;\u0026thinsp;1.72.\u003c/strong\u003e The interaction between copper oxide and alpha-1-antitrypsin is due to the hydrogen bonding between the copper oxide and LEU318 and LEU327.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2) Binding Energy Comparison\u003c/h2\u003e\n \u003cp\u003eThe ideal nanoparticle will be the one having the minimum binding energy with alpha-1-antitrypsin.\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMinimum Binding Energy of Each Nanoparticle\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNanoparticle\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMinimum Binding Energy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZinc Oxide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-2.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSilver Oxide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThird\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTitanium Oxide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-3.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCopper Oxide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFourth\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eFrom the table above (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) it is observed that titanium oxide is the ideal nanoparticle to be used for the molecular docking of alpha-1-antitrypsin with a minimum binding energy of -3.07 and copper oxide is the least favorable nanoparticle as it has a minimum binding energy of -1.72.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3) ADMET Profiles of the Ligands\u003c/h2\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2:\u0026nbsp;\u003c/strong\u003eSelected in-silico ADMET properties of the ligands\u003c/p\u003e\u0026nbsp;\n\u003c/div\u003e\n\u003ctable style=\"width: 4.7e+2pt;margin-left:8.5pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 63pt;border: 1.5pt solid black;padding: 0in;height: 39.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.45pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eADMET\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:0in;margin-right:7.8pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003epredicted profile\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:0in;margin-right:6.05pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eclassificat ions\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:10.5pt;margin-right:8.05pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eHuman Intestinal Absorptio n\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 195pt;border-top: 1.5pt solid black;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-image: initial;border-left: none;padding: 0in;height: 39.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.45pt;margin-right:19.25pt;margin-bottom:.0001pt;margin-left:29.1pt;text-indent:-9.3pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:17px;color:black;\"\u003eTitanium\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Zinc Oxide Oxide\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 207pt;border-top: 1.5pt solid black;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-image: initial;border-left: none;padding: 0in;height: 39.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.45pt;margin-right:0in;margin-bottom:.0001pt;margin-left:17.25pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:17px;color:black;\"\u003eSilver Oxide\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Copper Oxide\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.6pt;margin-right:3.25pt;margin-bottom:.0001pt;margin-left:3.7pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eValue\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.6pt;margin-right:6.25pt;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eProbabil ity\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.6pt;margin-right:19.15pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eValue\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.6pt;margin-right:3.5pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eProbabil ity\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.6pt;margin-right:18.65pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eValue\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.6pt;margin-right:4.0pt;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eProbabil ity\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.6pt;margin-right:19.15pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eValue\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.6pt;margin-right:3.5pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eProbabil ity\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.7pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.7pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9619\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.7pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.7pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9769\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.7pt;margin-right:21.1pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.7pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9769\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.7pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.7pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9769\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 63pt;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-left: 1.5pt solid black;border-image: initial;border-top: none;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:22.05pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eBlood Brain Barrier\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9750\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9750\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:21.1pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9750\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;padding: 0in;height: 51.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.4pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9750\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 63pt;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-left: 1.5pt solid black;border-image: initial;border-top: none;padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:6.05pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eHuman oral bioavailab ility\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7857\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7571\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:21.1pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.8143\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 64.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.05pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.8143\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 63pt;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-left: 1.5pt solid black;border-image: initial;border-top: none;padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:6.05pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eHepatotox icity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9250\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:21.1pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.925\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.9125\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 63pt;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-left: 1.5pt solid black;border-image: initial;border-top: none;padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:6.05pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eRespirator y toxicity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7556\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:23.0pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.8444\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:22.5pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.8444\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:23.0pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.8444\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 63pt;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-left: 1.5pt solid black;border-image: initial;border-top: none;padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:6.05pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eReproduct ive toxicity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.8111\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:23.0pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:22.5pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:23.0pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 51.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.2pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 63pt;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-left: 1.5pt solid black;border-image: initial;border-top: none;padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:4.2pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eMitochond rial toxicity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.5500\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:23.0pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7375\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:22.5pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7375\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:23.0pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e-\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(217, 233, 211);padding: 0in;height: 50.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:4.85pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7375\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 63pt;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-left: 1.5pt solid black;border-image: initial;border-top: none;padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:4.7pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eNephrotox icity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.8215\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7375\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:21.1pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7316\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.5pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.7316\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 63pt;border-right: 1.5pt solid black;border-bottom: 1.5pt solid black;border-left: 1.5pt solid black;border-image: initial;border-top: none;padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:6.05pt;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003eBiodegrad ation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:1.0pt;text-align:center;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.75in;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.7pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.6750\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.6500\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:21.1pt;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.95pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.6500\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:.3in;margin-bottom:.0001pt;margin-left:0in;text-align:right;border:none;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e+\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51pt;border-top: none;border-left: none;border-bottom: 1.5pt solid black;border-right: 1.5pt solid black;background: rgb(244, 204, 204);padding: 0in;height: 37.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Times New Roman\",serif;margin-top:5.35pt;margin-right:0in;margin-bottom:.0001pt;margin-left:4.45pt;border:none;'\u003e\u003cspan style=\"font-size:16px;color:black;\"\u003e0.6500\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePhysicochemical predictions of the ligands\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eProperty\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValue for Titanium Oxide\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValue for Zinc Oxide\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValue for Silver Oxide\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValue for\u003c/p\u003e\n \u003cp\u003eCopper Oxide\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMolecular Weight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e123.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlogP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH-Bond Acceptor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH-Bond Donor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRotatable bond\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eApplicability Domain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIn Domain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIn Domain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIn Domain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIn Domain\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eThe parameters linked with the blood-brain barrier, human intestinal absorption (HIA) and other toxicity tests were examined in order to analyze the absorption of ligands (nanoparticles). The values for the given nanoparticles were approximately in same range with less value variation. The blood-brain barrier (BBB) was examined in relation to medication distribution \u003cem\u003e(\u003c/em\u003ePujari et al. \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e). Because the blood-brain barrier tells us whether or not the nanoparticles will cross the brain barrier, it is crucial. The value for blood-brain barrier for all the nanoparticles is 0.9750. This shows that the nanoparticles can easily pass through the blood brain barrier and bind bind with alpha-1-antitrypsin. The human intestinal absorption value for the ligands falls in the acceptable range which is 0.5-1. The ligands within the acceptable range can easily pass from the intestine to the blood stream. Human intestinal absorption is an essential to determine whether the drug will reach its target (Yan A et al. \u003cspan class=\"CitationRef\"\u003e2008\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4) Conclusion","content":"\u003cp\u003eEarly detection of stroke can be possible by using the proteins expressed in blood as a biomarker. Alpha-1-antitrypsin is one of the proteins expressed as a result of inflammation caused by the depletion of oxygen in the brain. In this study, computational docking was performed to show the interaction of alpha-1-antitrypsin with four ligands which are namely zinc oxide, titanium oxide, copper oxide and silver oxide. Compared to the other nanoparticles titanium oxide exhibited a low binding energy of -3.07 kcal/mol. ADMET studies were also done to find the toxicity levels of the ligands. One of the essential results of the ADMET studies was the blood brain barrier value. Blood brain barrier(BBB) is a semipermeable membrane which plays a major role in the movement of ions and molecules between the blood and brain. The BBB value for all the ligands was high meaning that the nanoparticles can easily pass through the brain and bind with alpha-1-antitrypsin at the site of inflammation. The results from the molecular docking and the ADMET studies shows that titanium oxide is comparatively the best ligand to bind with alpha-1-antitrypsin. Our future studies will include an in vitro study on the binding of alpha-1-antitrypsin and titanium oxide nanoparticles. This study will open new windows in healthcare centers by introducing a non-invasive method of detecting stroke during the early stage.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e1. Ms. Lakshmi Sundeep developed the proof of concept2. Mariamawit wrote the main manuscript text3. Dr. J.Saktidasan prepared all the figures4. All authors reviewed the manuscript5. Dr. J Sandhya developed the tables\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBarthels D, Das H (2020) Current advances in ischemic stroke research and therapies. 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Int J Mol Sci 9(10):1961\u0026ndash;1976. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/ijms9101961\u003c/span\u003e\u003cspan address=\"10.3390/ijms9101961\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin ZF, Wu L, Yang HG, Su YH (2013) Recent progress in biomedical applications of titanium dioxide. Phys Chem Chem Phys 15(14):4844\u0026ndash;4858\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Nanoparticles, Alpha-1-antitrypsin, Stroke, Molecular docking, ADMET, Nanotechnology, Biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-4422570/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4422570/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eStroke causes a large number of deaths yearly since it is not detected early. Stroke is caused by the narrowing of the blood vessels and reducing the flow of blood and oxygen to the brain. When ischemic stroke is about to occur some proteins are expressed making them a potential biomarker. The biomarker we chose to work with is alpha-1-antitrypsin because there are studies showing the correlation of alpha-1-antitrypsin with the acute stage of stroke. Due to the inflammation caused during stroke, there will be a rise in alpha-1-antitrypsin. By docking alpha-1-antitrypsin with nanoparticles we can use them as a diagnostic tool for stroke. Nanoparticles have shown a promising result in detection of cancer, arthritis and other infectious disease making it a potential ligand. From this study titanium oxide showed the lowest binding energy and showed lower toxicity compared to the other nanoparticles used in the study. By performing further studies, binding of alpha-1-antitrypsin and titanium oxide can be used for the detection of stroke at the early stage.\u003c/p\u003e","manuscriptTitle":"Comparative Molecular Docking and ADMET Studies of Alpha-1-antitrypsin with Nanoparticles","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-27 05:38:14","doi":"10.21203/rs.3.rs-4422570/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e9813e40-51fa-4b9e-a59e-32edb97e7b83","owner":[],"postedDate":"May 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-10T03:17:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-27 05:38:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4422570","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4422570","identity":"rs-4422570","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}