Triple Targeting of Human IMPDH and Both RdRps of SARS-CoV-2 and Rhizopus Oryzae: An in Silico Perspective

Triple Targeting of Human IMPDH and Both RdRps of SARS-CoV-2 and Rhizopus Oryzae: An in Silico Perspective | 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 Triple Targeting of Human IMPDH and Both RdRps of SARS-CoV-2 and Rhizopus Oryzae: An in Silico Perspective Abdel_moniem S Hassan, Abdo A Elfiky, Alaa Elgohary This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-863321/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 Mucormycosis has been reported in many regions associated with SARS-CoV-2 infections during the past few months. The viral RNA-dependent RNA polymerase (RdRp) is a crucial protein target in viral and fungal pathogens. Molecular docking combined with molecular dynamics simulation (MDS) is utilized to test nucleotide-based inhibitors against the RdRps of SARS-CoV-2 solved structure and Rhizopus oryzae RdRp model built in silico . Additionally, the human Inosine monophosphate dehydrogenase (IMPDH) was targeted by the same inhibitors. The results reveal a comparable binding affinity of four nucleotide derivatives compared to remdesivir and sofosbuvir against both IMPDH and the RdRps of SARS-CoV-2 and Rhizopus oryzae , the main causing agent of mucormycosis. The binding affinities are calculated using different conformations of the RdRps after 100 ns MDS and trajectories clustering. The present study suggests the triple inhibition potential of four nucleotide inhibitors against SARS-CoV-2 & R. oryzae RdRps and the human IMPDH, while experimental validation is yet to be performed. Medicinal Chemistry Mucormycosis SARS-CoV-2 computational drug design Nucleotide inhibitors RdRp IMPDH Figures Figure 1 Figure 2 Figure 3 Introduction: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its associated pneumonia (COVID-19) caused health and economic burdens during the last two years. The currently developed pandemic of Mucormycosis in COVID-19 patients and COVID-19 recovered people is causing a debate about the therapeutics approved against COVID-19 ( 1 – 3 ). Several in silico studies are able to suggest possible medicines against COVID-19 even before the deposition of any solved structures for the viral proteins ( 4 – 6 ). Some of the recommended drugs are now approved by the Food and Drugs Administration (FDA) and save lives ( 6 – 8 ). The viral RNA-dependent RNA polymerase (RdRp) is one of the most targeted viral proteins in many diseases caused by RNA viruses ( 6 , 9 – 12 ). The active site aspartates of the RdRp is very conserved even in fungal species of Mucorales ( 13 ). On the other hand, the human Inosine monophosphate dehydrogenase (IMPDH) has been identified as a key enzyme in cell proliferation and differentiation regulation ( 14 , 15 ). IMPDH has recently emerged as an important therapeutic target in the expedition to discover drugs belonging to the immunosuppressive, antiviral, antimicrobial, and anticancer therapeutic era. IMPDH catalyzes the de novo synthesis of purine (guanine) nucleotides, the nicotinamide adenine dinucleotide (NAD)-dependent oxidation of inosine 5-monophosphate (IMP) to xanthosine 5-monophosphate (XMP). The first step of IMPDH reaction involves the attack of catalytic (Cys331) on substrate IMP followed by hydride transfer to NAD+, forming the covalent intermediate E-XMP*. E-XMP* is hydrolyzed during the second step, yielding the product XMP ( 16 , 17 ). Inhibition of IMPDH produces an overall reduction in guanine nucleotide pools. Subsequent interruption of DNA and RNA synthesis results in cytotoxicity inhibition of IMPDH is also used as a strategy in immuno- suppressive therapy. The growth and differentiation of human lymphocytes are particularly dependent on the IMPDH- catalyzed de novo pathway for purine nucleotide synthesis ( 18 ). Inhibition of IMPDH leads to suppression of both T and B lymphocyte proliferation. For compounds targeting the IMP-binding site, development has focused on the nucleotide analog. The competitive IMPDH inhibitors for IMP, such as ribavirin ( 19 ) and mizoribine ( 20 ), are nucleoside analogs that undergo phosphorylation to the active inhibitor (triphosphate) in vivo . Thuringiensin (Thu), also known as β-exotoxin, is a thermostable secondary metabolite secreted by Bacillus thuringiensis . It has insecticidal activity against many insects, including species belonging to the orders Diptera, Coleoptera, Lepidoptera, Hymenoptera, Orthoptera, and Isoptera, and several nematode species. The insecticidal mechanism of Thu is not fully understood. However, it is known to be an ATP analog ( 21 ). The chemical formula of Thu is C 22 H 32 O 19 N 5 P, and it is composed of adenosine, glucose, phosphoric acid, and gluconic diacid. Thu inhibits RNA synthesis by competing with ATP on binding sites, affecting insect molting & pupation, and causing teratological effects at sublethal doses ( 22 – 24 ). In this study, our approach is to test four nucleotide inhibitors based on Thu against the RdRps of SARS-CoV-2 and Rhizopus oryzae in addition to the human IMPDH. Molecular docking combined with dynamics simulation emphasizes the binding effectiveness using computational tools that are yet to be validated experimentally. Materials And Methods: Structural retrieval and preparations Thuringiensin (CID: 20056441) and its analogs were retrieved from the PubChem database in the SDF format then converted to PDB using Open Babel software ( 25 , 26 ). These analogs include Thuringiensin 6,3-Lactone (CID: 102074352), 2-[(2R,3R,4R,5S,6R)-5-[[(2R,3S,4R,5R)-5-(6-Aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy]-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-4-phosphonooxyhexanedioic acid (CID: 99213), and Adenosine 5'-(tetrahydrogentriphosphate), 5'-6-ester with D-glucose (CID: 194147). Sofosbuvir and Remdesivir are used as positive controls. AutoDock Tools 1.5.6 software was utilized to prepare the ligands for the docking ( 27 ). Kollman and Gasteiger charges were added to the ligands, and then the PDBQT files were generated for the docking experiments. On the other hand, the three-dimensional structures of the receptors were retrieved from the Protein Data Bank ( http://www.rcsb.org//pdb ) ( 28 ). The selected PDB files for the SARS-CoV-2 RdRp and the human IMPDH were 7BTF and 1NF7, respectively ( 29 ). No solved structure was deposited yet for the R. oryzae RdRp in the protein data bank, so we used the previously in silico generated all-atoms 3D-model by the Swiss Model webserver ( 13 , 30 ). This model was subjected to 100 ns MDS in a previous study and clustered through UCSF Chimera software ( 31 ). Seven different conformations of the R. oryzae model representing the most populated clusters are tested against the inhibitors. The structure 7BTF was subjected in a previous study to 100 ns MDS and then clustered into ten clusters (see Figure S1). We use the representative structure from each cluster to test the binding of the nucleotide inhibitors. Molecular docking The receptors were stored in PDB format after removing the water molecules and ligands with PyMOL software ( 32 ). Then polar hydrogen atoms and Kollman charges were added to the receptors using Autodock Tools 1.5.6 then saved in PDBQT format for the docking experiments. Autodock Vina was used for the docking of the ligands to the receptor using flexible ligands and a flexible active site protocol ( 33 ). The grid box was centered at the active residues (D760 & D761 for SARS-CoV-2 RdRp and D193 & D194 for R. oryzae RdRp), defined by the native co-crystallized ligands, while box size was set to (40 × 40 × 40) Å 3 . On the other hand, the grid box size for the human IMPDH was set to be (40 × 60 × 64) Å 3 and centered at (76.7, 83.8, 53.9). The active site for the human IMPDH was S68, N303, R322, S388, Y411, M414, and Q441. Other docking parameters were set to default while the exhaustiveness value was adjusted to 8 in all the docking trials. Discovery studio software is utilized to analyze the docking complexes ( 34 ). Results And Discussion In the current study, four nucleotide inhibitors are tested against both host-cell (Inosine monophosphate dehydrogenase) and pathogen's proteins (RNA-dependent RNA polymerase). These proteins proved their effectiveness as drug targets ( 6 , 13 , 35 , 36 ). Figure 1 shows the 2D structures of the four nucleotide inhibitors which are Thuringiensin derivatives (CID: 99213, 194147, 20056441, and 102074352) and the positive control drugs (Sofosbuvir and Remdesivir). The FDA approves these drugs against RNA viruses such as Hepatitis C Virus, Ebola virus, and SARS-CoV-2 ( 37 – 41 ). The four Thuringiensin derivatives are based on the nucleotide adenosine (A), where the added moieties are present at the 5' position of the ribose ring. On the other hand, the positive controls drugs (remdesivir and Sofosbuvir) are adenosine triphosphate modified at position 1' of the ribose (C ≡ N) and uridine derivative modified at position 1' of the ribose (F, methyl), respectively. Binding affinities of the nucleotide inhibitors against the pathogenic proteins As shown in Fig. 2 , the average binding affinities of the four nucleotide inhibitors (blue columns) (CID: 99213, 194147, 20056441, and 102074352) against SARS-CoV-2 RdRp (A), Rhizopus oryzae RdRp (B), and the human IMPDH (C) are in the same range of the positive control drugs. In Fig. 2 , the error bars represent the standard deviations. Red columns in Fig. 2 represent the positive control drugs (Sofosbuvir and Remdesivir). The docking trials are performed on different conformations of the RdRp proteins generated from the 100 ns MDS runs, while Each conformation resembles a cluster from the trajectories. The MDS's role was to equilibrate the protein systems and ensure different possible conformations during the simulation period. The average binding affinity for the four nucleotide inhibitors lies between − 6.84 kcal/mol (194147 versus SARS-CoV-2 RdRp) and − 9.8 kcal/mol (102074352 versus human IMPDH). For the SARS-CoV-2 RdRp, the average binding affinity for the four nucleotide inhibitors is -7.24 kcal/mol, while the average binding affinities of sofosbuvir and remdesivir against SARS-CoV-2 RdRp are − 7.4 and − 7.3 kcal/mol, respectively. Additionally, the average binding affinity of the four nucleotide inhibitors against R. oryzae RdRp is -7.63 kcal/mol, while it is -8.06 and − 7.8 kcal/mol for the sofosbuvir and remdesivir, respectively. These values indicate that the Thuringiensin derivatives have comparable average binding affinities to that of Sofosbuvir and Remdesivir against the viral and fungal RdRps. On the other hand, the average binding affinity of the four nucleotide inhibitors against the human IMPDH is -8.71 kcal/mol, which is lower (better) than the average binding affinity of the positive controls (-8.3 and − 7.85 kcal/mol for sofosbuvir and remdesivir, respectively). The best compound from the Thuringiensin derivatives in binding all the proteins is the Thuringiensin 6,3-lactone (CID: 102074352). In order to check the binding mode of each ligand to the three proteins, the interaction map of the complexes is mined by the Discovery studio software. Based on the analysis, the compounds' binding modes against SARS-CoV-2 RdRp, R. oryzae RdRp, and human IMPDH are explored and tabulated. Table 1 lists the interactions established for each ligand (Thuringiensin derivatives and the positive control drugs) after docking to the active site of the proteins. The main type of interaction that formed upon docking is the formation of Hydrogen bonds (H-bonds). An average of 13 H-bonds is formed between the positive control drugs and the protein. For the Thuringiensin derivatives, the average number of H-bonds formed is 14, while few hydrophobic contacts, salt bridges (red), and halogen bonds (green) are reported in Table 1 . The residues shown in bold are the active site residues in each protein. For example, the most-reported residues from SARS-CoV-2 RdRp that take part in the interactions with the nucleotide inhibitors are D760( 12 ), D761( 9 ), D618( 9 ), R555( 8 ), E811( 6 ), S814( 6 ), and Y619( 5 ), ranked by the number of reported interaction established upon docking. For the R. oryzae RdRp, the most reported residues to interact with the fungal RdRp are E27( 15 ), D56( 12 ), R14( 10 ), D193( 8 ), G142( 5 ), S146( 5 ), D194( 5 ). On the other hand, the residues from the human IMPDH that reported to interact with the nucleotide inhibitors are D364( 14 ), D274( 12 ), S276( 8 ), H93( 6 ), G326( 6 ), D256( 5 ), C331( 5 ), and T333( 5 ). Table 1 The interactions that were established after docking the four adenosine derivatives and positive controls (Sofosbuvir and Remdesivir) into the SARS-CoV-2 RdRp, Rhizopus oryzae RdRp, and the human IMPDH. Red-colored residues are residues that interact with salt bridges, while green-colored residues are that interact through halogen bonds. Bold residues are the active residues in each protein. Protein target Compound Binding affinity (kcal/mol) H-bonding Hydrophobic interaction number Amino acids involved number Amino acids involved SARS-CoV-2 RdRp Sofosbuvir -7.4 8 S549, R555(2), R555, Y619, K621, C622, D623, and N691 Remdesivir -7.3 10 K551, R555(2), D618, Y619, K621, K621, D760(4), D761(2) , and S814 1 K551 CID: 99213 -7.4 11 D618(4), Y619, C622, D761(2) , W800, and E811(2) CID: 194147 -6.9 14 K551(3), R555, W617, Y619(2), D760 , W800, E811(2), S814(2), and R836 CID: 20056441 -7.1 18 R555(2), D618(3), D623, D760(6), D761(4) , and S814(2) CID: 102074352 -7.4 8 K551, D618, D760, D761 , W800, E811(2), and S814 Rhizopus oryzae RdRp Sofosbuvir -8.0 11 P10, R14, Q141(2), S146, D193(3) , and D194(3) 4 A11, Y13(2), and Y150 Remdesivir -7.9 11 E27(2), Q31, S53, D56(2), Y191, D193(2) , and D194(2) 5 N12, R14, and E27(3) CID: 99213 -7.1 17 R14(2), E27(5), D56(4), Y88, G142, S146(3), and D193 CID: 194147 -7.2 15 R14(3), E27(2), D56(4), Q57, G142(2), S143(2), and Y191 CID: 20056441 -7.5 15 R14(2), D83(2), S86(2), Y88, T90, G142(2), P147(2), D193(2) , and W222 1 W222 CID: 102074352 -8.3 12 Y13, R14, E27(3), D56(2), Y88, Q141(2), S143, and S146 Human IMPDH Sofosbuvir -8.0 15 D274(2), S276(2), M325, G326, S327, G328, C331, D364(4), G415(2), K438, and G442 Remdesivir -7.8 23 D274(4), S276(3), R322 , G324(2), M325(2), G326(2), S327, C331, D364(2), M414 , G415, K438(2), and Q441 1 D274 CID: 99213 -8.4 12 S68(2) , D256(2), D274, S276, R322 , G326, C331, T333, and D364(2) CID: 194147 -7.3 17 S68 , H93, D274(4), S275(2), S276, G326, S327, C331, T333, and D364(4) CID: 20056441 -8.3 15 H93(2), N94, D256(2), R259, S276, N303 , G324(2), G326, S327, T333(2), and D364 3 H93(3) CID: 102074352 -9.8 11 T252(2), D256, S275(2), Q277, N303 , R322 , C331, T333, and D364 Figure 3 shows the interactions that established between Thuringiensin 6,3-lactone (CID: 102074352), and the SARS-CoV-2 RdRp (top left), R. oryzae RdRp (top write), and the human IMPDH (down). This compound shows the best average binding affinities against the three proteins (see Fig. 2 ) compared to other nucleotide inhibitors. Figure 3 is represented by Discovery studio software, where the ligand is shown in the sticks, and the interacting residues are depicted in lines. The only type of interaction is the formation of H-bonds (dashed lines). Thuringiensin 6,3-lactone (CID: 102074352) formed 8 H-bonds to SARS-CoV-2 RdRp with residues K551, D618, D760, D761, W800, E811( 2 ), and S814. For R. oryzae RdRp Y13, R14, E27( 3 ), D56( 2 ), Y88, Q141( 2 ), S143, and S146 formed 12 H-bonds with Thuringiensin 6,3-lactone. At the same time, residues T252( 2 ), D256, S275( 2 ), Q277, N303, R322, C331, T333, and D364 of the human IMPDH formed 11 H-bonds with Thuringiensin 6,3-lactone. The current work reveals the favorable binding affinity of four adenosine derivatives against the SARS-CoV-2 RdRp, Rhizopus oryzae RdRp, and the human IMPDH. Thuringiensin 6,3-lactone has the best binding affinity to the three proteins, hence can be a potential inhibitor against COVID-19/Mucormycosis coinfection, while experimental validation is yet to be performed. Conclusion: Remdesivir proves its effectiveness against COVID-19 (reducing the hospitalization time). Four Thuringiensin derivatives (adenosine based) are tested against SARS-CoV-2 RdRp, Rhizopus oryzae RdRp, and the human IMPDH using in silico techniques. The results reveal the binding potential of the Thuringiensin derivatives against the viral, fungal, and human proteins. These adenosine derivatives can be potential inhibitors of the dual SARS-CoV-2 (COVID-19) R. oryzae (Mucormycosis) coinfection. Further, in vitro and other experimental validations are suggested for the best compound (Thuringiensin 6,3-lactone) as future work. Declarations Conflict of interest: All the authors declare no conflict of interest in this work. 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Phytomedicine 85:153310 Supplementary Files FigureS1A.tif FigureS1B.tif FigureS1C.tif Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-863321","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":49593577,"identity":"a5029856-3494-4b6d-b303-4249d777f3fd","order_by":0,"name":"Abdel_moniem S Hassan","email":"","orcid":"","institution":"Fayoum University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Abdel_moniem","middleName":"S","lastName":"Hassan","suffix":""},{"id":49593578,"identity":"739dcfbc-2f75-4b52-a5f9-8ceb81690d1a","order_by":1,"name":"Abdo A Elfiky","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYDACCQYDhg8MDDwQHhuRWhhnkKyFmQfOI0YL/+zmjY9t/tjJMLCfAbqw7DADP/8CApbcOVZsnNuWzMPAkwN04bnDDJIzHhCw5kaOmXRuwwEeBgkeA2betsMMBjcO4NchD9Ji8Qeq5S9Qiz0hLQYgLQxsUC2MIFv4G/BrMQT6xbAX6Bc2nrSCgz3n0nkkbhDwitzt5o0Pfvyxs+dnPwxklFnL8fcTcBgcgGIEpBbowgQitSAAP7G2jIJRMApGwUgBAMmoPGRTTpRXAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4600-6240","institution":"Cairo University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Abdo","middleName":"A","lastName":"Elfiky","suffix":""},{"id":49593579,"identity":"c94f1af9-25f3-44ad-aa4e-213ebbb8c507","order_by":2,"name":"Alaa Elgohary","email":"","orcid":"","institution":"Cairo University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alaa","middleName":"","lastName":"Elgohary","suffix":""}],"badges":[],"createdAt":"2021-09-01 05:50:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-863321/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-863321/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":13069733,"identity":"3163938d-51f2-49c9-896d-bbd01bd128d6","added_by":"auto","created_at":"2021-09-03 21:46:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":164659,"visible":true,"origin":"","legend":"2D structures show the four Thuringiensin derivatives and the positive control drugs Sofosbuvir and Remdesivir with PubChem accession numbers.","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-863321/v1/aafd6b53411785102c04ae75.png"},{"id":13069731,"identity":"61e52e4a-caaa-4bc4-b0b2-24e5d5eae510","added_by":"auto","created_at":"2021-09-03 21:46:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":463680,"visible":true,"origin":"","legend":"The average binding affinities (in kcal/mol) for the four adenosine derivatives (blue columns) and the positive controls (red columns) against (A) SARS-CoV-2 RdRp, (B) Rhizopus oryzae RdRp, and (C) the human IMPDH. Error bars resemble the standard deviation (SD) of the mean. Different conformations of the proteins are used in the docking experiments after MDS cluster analysis. ","description":"","filename":"OnlineFigure2A.png","url":"https://assets-eu.researchsquare.com/files/rs-863321/v1/135b8e4559fb303bd925ec58.png"},{"id":13069715,"identity":"aad47c46-f75c-4135-a5eb-34f9aa8143bb","added_by":"auto","created_at":"2021-09-03 21:46:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":245223,"visible":true,"origin":"","legend":"The interaction patterns for the best adenosine derivative (Thuringiensin 6,3-lactone) after docking into the active site of SARS-CoV-2 RdRp (top left), Rhizopus oryzae RdRp (top right), and the human IMPDH (bottom). The residues from the proteins that form contacts to the ligands are depicted in lines, while the ligands are in the sticks. H-bonds are shown in dashed lines.","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-863321/v1/2fe83bbf6e3a69d8b6db020c.png"},{"id":13713033,"identity":"f2bb06d9-0a73-47ca-a369-972e5577878a","added_by":"auto","created_at":"2021-09-17 14:30:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1256405,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-863321/v1/7f0797de-1440-4492-993a-808ba46e9093.pdf"},{"id":13069714,"identity":"e1859aac-38b7-4c7d-8d09-7aaf6f9836eb","added_by":"auto","created_at":"2021-09-03 21:46:03","extension":"tif","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":819888,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS1A.tif","url":"https://assets-eu.researchsquare.com/files/rs-863321/v1/cffaca77e75d0847c97989a2.tif"},{"id":13069713,"identity":"dcf83f2e-8617-4eb7-91ea-e49eea50259a","added_by":"auto","created_at":"2021-09-03 21:46:03","extension":"tif","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":609268,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS1B.tif","url":"https://assets-eu.researchsquare.com/files/rs-863321/v1/0618b115f51bf62b5e2bf252.tif"},{"id":13069728,"identity":"a23b4aa0-d3c0-4cef-bc19-a34a8b53b661","added_by":"auto","created_at":"2021-09-03 21:46:15","extension":"tif","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":628104,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS1C.tif","url":"https://assets-eu.researchsquare.com/files/rs-863321/v1/e8c8d00a1d6d1aad0c95eb55.tif"}],"financialInterests":"","formattedTitle":"\u003cp\u003eTriple Targeting of Human IMPDH and Both RdRps of SARS-CoV-2 and Rhizopus Oryzae: An in Silico Perspective\u003c/p\u003e","fulltext":[{"header":"Introduction:","content":"\u003cp\u003eSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its associated pneumonia (COVID-19) caused health and economic burdens during the last two years. The currently developed pandemic of Mucormycosis in COVID-19 patients and COVID-19 recovered people is causing a debate about the therapeutics approved against COVID-19 (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Several \u003cem\u003ein silico\u003c/em\u003e studies are able to suggest possible medicines against COVID-19 even before the deposition of any solved structures for the viral proteins (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Some of the recommended drugs are now approved by the Food and Drugs Administration (FDA) and save lives (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe viral RNA-dependent RNA polymerase (RdRp) is one of the most targeted viral proteins in many diseases caused by RNA viruses (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The active site aspartates of the RdRp is very conserved even in fungal species of Mucorales (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). On the other hand, the human Inosine monophosphate dehydrogenase (IMPDH) has been identified as a key enzyme in cell proliferation and differentiation regulation (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). IMPDH has recently emerged as an important therapeutic target in the expedition to discover drugs belonging to the immunosuppressive, antiviral, antimicrobial, and anticancer therapeutic era. IMPDH catalyzes the \u003cem\u003ede novo\u003c/em\u003e synthesis of purine (guanine) nucleotides, the nicotinamide adenine dinucleotide (NAD)-dependent oxidation of inosine 5-monophosphate (IMP) to xanthosine 5-monophosphate (XMP). The first step of IMPDH reaction involves the attack of catalytic (Cys331) on substrate IMP followed by hydride transfer to NAD+, forming the covalent intermediate E-XMP*. E-XMP* is hydrolyzed during the second step, yielding the product XMP (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInhibition of IMPDH produces an overall reduction in guanine nucleotide pools. Subsequent interruption of DNA and RNA synthesis results in cytotoxicity inhibition of IMPDH is also used as a strategy in immuno- suppressive therapy. The growth and differentiation of human lymphocytes are particularly dependent on the IMPDH- catalyzed \u003cem\u003ede novo\u003c/em\u003e pathway for purine nucleotide synthesis (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Inhibition of IMPDH leads to suppression of both T and B lymphocyte proliferation. For compounds targeting the IMP-binding site, development has focused on the nucleotide analog. The competitive IMPDH inhibitors for IMP, such as ribavirin (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) and mizoribine (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), are nucleoside analogs that undergo phosphorylation to the active inhibitor (triphosphate) \u003cem\u003ein vivo\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eThuringiensin (Thu), also known as β-exotoxin, is a thermostable secondary metabolite secreted by Bacillus \u003cem\u003ethuringiensis\u003c/em\u003e. It has insecticidal activity against many insects, including species belonging to the orders Diptera, Coleoptera, Lepidoptera, Hymenoptera, Orthoptera, and Isoptera, and several nematode species. The insecticidal mechanism of Thu is not fully understood. However, it is known to be an ATP analog (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The chemical formula of Thu is C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e32\u003c/sub\u003eO\u003csub\u003e19\u003c/sub\u003eN\u003csub\u003e5\u003c/sub\u003eP, and it is composed of adenosine, glucose, phosphoric acid, and gluconic diacid. Thu inhibits RNA synthesis by competing with ATP on binding sites, affecting insect molting \u0026amp; pupation, and causing teratological effects at sublethal doses (\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, our approach is to test four nucleotide inhibitors based on Thu against the RdRps of SARS-CoV-2 and Rhizopus \u003cem\u003eoryzae\u003c/em\u003e in addition to the human IMPDH. Molecular docking combined with dynamics simulation emphasizes the binding effectiveness using computational tools that are yet to be validated experimentally.\u003c/p\u003e"},{"header":"Materials And Methods:","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStructural retrieval and preparations\u003c/h2\u003e \u003cp\u003eThuringiensin (CID: 20056441) and its analogs were retrieved from the PubChem database in the SDF format then converted to PDB using Open Babel software (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). These analogs include Thuringiensin 6,3-Lactone (CID: 102074352), 2-[(2R,3R,4R,5S,6R)-5-[[(2R,3S,4R,5R)-5-(6-Aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy]-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-4-phosphonooxyhexanedioic acid (CID: 99213), and Adenosine 5'-(tetrahydrogentriphosphate), 5'-6-ester with D-glucose (CID: 194147). Sofosbuvir and Remdesivir are used as positive controls. AutoDock Tools 1.5.6 software was utilized to prepare the ligands for the docking (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Kollman and Gasteiger charges were added to the ligands, and then the PDBQT files were generated for the docking experiments.\u003c/p\u003e \u003cp\u003eOn the other hand, the three-dimensional structures of the receptors were retrieved from the Protein Data Bank (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.rcsb.org//pdb\u003c/span\u003e\u003c/span\u003e) (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The selected PDB files for the SARS-CoV-2 RdRp and the human IMPDH were 7BTF and 1NF7, respectively (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). No solved structure was deposited yet for the R. \u003cem\u003eoryzae\u003c/em\u003e RdRp in the protein data bank, so we used the previously \u003cem\u003ein silico\u003c/em\u003e generated all-atoms 3D-model by the Swiss Model webserver (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). This model was subjected to 100 ns MDS in a previous study and clustered through UCSF Chimera software (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Seven different conformations of the R. \u003cem\u003eoryzae\u003c/em\u003e model representing the most populated clusters are tested against the inhibitors. The structure 7BTF was subjected in a previous study to 100 ns MDS and then clustered into ten clusters (see Figure S1). We use the representative structure from each cluster to test the binding of the nucleotide inhibitors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMolecular docking\u003c/h2\u003e \u003cp\u003eThe receptors were stored in PDB format after removing the water molecules and ligands with PyMOL software (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Then polar hydrogen atoms and Kollman charges were added to the receptors using Autodock Tools 1.5.6 then saved in PDBQT format for the docking experiments. Autodock Vina was used for the docking of the ligands to the receptor using flexible ligands and a flexible active site protocol (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The grid box was centered at the active residues (D760 \u0026amp; D761 for SARS-CoV-2 RdRp and D193 \u0026amp; D194 for R. \u003cem\u003eoryzae\u003c/em\u003e RdRp), defined by the native co-crystallized ligands, while box size was set to (40 \u0026times; 40 \u0026times; 40) \u0026Aring;\u003csup\u003e3\u003c/sup\u003e. On the other hand, the grid box size for the human IMPDH was set to be (40 \u0026times; 60 \u0026times; 64) \u0026Aring;\u003csup\u003e3\u003c/sup\u003e and centered at (76.7, 83.8, 53.9). The active site for the human IMPDH was S68, N303, R322, S388, Y411, M414, and Q441. Other docking parameters were set to default while the exhaustiveness value was adjusted to 8 in all the docking trials. Discovery studio software is utilized to analyze the docking complexes (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results And Discussion","content":"\u003cp\u003eIn the current study, four nucleotide inhibitors are tested against both host-cell (Inosine monophosphate dehydrogenase) and pathogen's proteins (RNA-dependent RNA polymerase). These proteins proved their effectiveness as drug targets (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the 2D structures of the four nucleotide inhibitors which are Thuringiensin derivatives (CID: 99213, 194147, 20056441, and 102074352) and the positive control drugs (Sofosbuvir and Remdesivir). The FDA approves these drugs against RNA viruses such as Hepatitis C Virus, Ebola virus, and SARS-CoV-2 (\u003cspan additionalcitationids=\"CR38 CR39 CR40\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). The four Thuringiensin derivatives are based on the nucleotide adenosine (A), where the added moieties are present at the 5' position of the ribose ring. On the other hand, the positive controls drugs (remdesivir and Sofosbuvir) are adenosine triphosphate modified at position 1' of the ribose (C\u0026thinsp;\u0026equiv;\u0026thinsp;N) and uridine derivative modified at position 1' of the ribose (F, methyl), respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eBinding affinities of the nucleotide inhibitors against the pathogenic proteins\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the average binding affinities of the four nucleotide inhibitors (blue columns) (CID: 99213, 194147, 20056441, and 102074352) against SARS-CoV-2 RdRp (A), Rhizopus \u003cem\u003eoryzae\u003c/em\u003e RdRp (B), and the human IMPDH (C) are in the same range of the positive control drugs. In Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the error bars represent the standard deviations. Red columns in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e represent the positive control drugs (Sofosbuvir and Remdesivir). The docking trials are performed on different conformations of the RdRp proteins generated from the 100 ns MDS runs, while Each conformation resembles a cluster from the trajectories. The MDS's role was to equilibrate the protein systems and ensure different possible conformations during the simulation period.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe average binding affinity for the four nucleotide inhibitors lies between \u0026minus;\u0026thinsp;6.84 kcal/mol (194147 versus SARS-CoV-2 RdRp) and \u0026minus;\u0026thinsp;9.8 kcal/mol (102074352 versus human IMPDH). For the SARS-CoV-2 RdRp, the average binding affinity for the four nucleotide inhibitors is -7.24 kcal/mol, while the average binding affinities of sofosbuvir and remdesivir against SARS-CoV-2 RdRp are \u0026minus;\u0026thinsp;7.4 and \u0026minus;\u0026thinsp;7.3 kcal/mol, respectively. Additionally, the average binding affinity of the four nucleotide inhibitors against R. \u003cem\u003eoryzae\u003c/em\u003e RdRp is -7.63 kcal/mol, while it is -8.06 and \u0026minus;\u0026thinsp;7.8 kcal/mol for the sofosbuvir and remdesivir, respectively. These values indicate that the Thuringiensin derivatives have comparable average binding affinities to that of Sofosbuvir and Remdesivir against the viral and fungal RdRps.\u003c/p\u003e \u003cp\u003eOn the other hand, the average binding affinity of the four nucleotide inhibitors against the human IMPDH is -8.71 kcal/mol, which is lower (better) than the average binding affinity of the positive controls (-8.3 and \u0026minus;\u0026thinsp;7.85 kcal/mol for sofosbuvir and remdesivir, respectively). The best compound from the Thuringiensin derivatives in binding all the proteins is the Thuringiensin 6,3-lactone (CID: 102074352). In order to check the binding mode of each ligand to the three proteins, the interaction map of the complexes is mined by the Discovery studio software. Based on the analysis, the compounds' binding modes against SARS-CoV-2 RdRp, R. \u003cem\u003eoryzae\u003c/em\u003e RdRp, and human IMPDH are explored and tabulated.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e lists the interactions established for each ligand (Thuringiensin derivatives and the positive control drugs) after docking to the active site of the proteins. The main type of interaction that formed upon docking is the formation of Hydrogen bonds (H-bonds). An average of 13 H-bonds is formed between the positive control drugs and the protein. For the Thuringiensin derivatives, the average number of H-bonds formed is 14, while few hydrophobic contacts, salt bridges (red), and halogen bonds (green) are reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The residues shown in bold are the active site residues in each protein. For example, the most-reported residues from SARS-CoV-2 RdRp that take part in the interactions with the nucleotide inhibitors are D760(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), D761(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), D618(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), R555(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), E811(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), S814(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), and Y619(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), ranked by the number of reported interaction established upon docking. For the R. \u003cem\u003eoryzae\u003c/em\u003e RdRp, the most reported residues to interact with the fungal RdRp are E27(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), D56(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), R14(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), D193(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), G142(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), S146(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), D194(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). On the other hand, the residues from the human IMPDH that reported to interact with the nucleotide inhibitors are D364(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), D274(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), S276(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), H93(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), G326(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), D256(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), C331(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), and T333(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe interactions that were established after docking the four adenosine derivatives and positive controls (Sofosbuvir and Remdesivir) into the SARS-CoV-2 RdRp, Rhizopus oryzae RdRp, and the human IMPDH. Red-colored residues are residues that interact with salt bridges, while green-colored residues are that interact through halogen bonds. Bold residues are the active residues in each protein.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eProtein target\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBinding affinity (kcal/mol)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eH-bonding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c9\" namest=\"c7\"\u003e \u003cp\u003eHydrophobic interaction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003enumber\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eAmino acids involved\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003enumber\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003eAmino acids involved\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eSARS-CoV-2 RdRp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSofosbuvir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eS549, R555(2), R555, Y619, K621, C622, D623, and N691\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRemdesivir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eK551, R555(2), D618, Y619, K621, K621, \u003cb\u003eD760(4), D761(2)\u003c/b\u003e, and S814\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eK551\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 99213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eD618(4), Y619, C622, \u003cb\u003eD761(2)\u003c/b\u003e, W800, and E811(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 194147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eK551(3), R555, W617, Y619(2), \u003cb\u003eD760\u003c/b\u003e, W800, E811(2), S814(2), and R836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 20056441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR555(2), D618(3), D623, \u003cb\u003eD760(6), D761(4)\u003c/b\u003e, and S814(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eCID: 102074352\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-7.4\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eK551, D618, \u003cb\u003eD760, D761\u003c/b\u003e, W800, E811(2), and S814\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eRhizopus \u003cem\u003eoryzae\u003c/em\u003e RdRp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSofosbuvir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP10, R14, Q141(2), S146, \u003cb\u003eD193(3)\u003c/b\u003e, and \u003cb\u003eD194(3)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eA11, Y13(2), and Y150\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRemdesivir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eE27(2), Q31, S53, D56(2), Y191, \u003cb\u003eD193(2)\u003c/b\u003e, and \u003cb\u003eD194(2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN12, R14, and E27(3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 99213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR14(2), E27(5), D56(4), Y88, G142, S146(3), and \u003cb\u003eD193\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 194147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR14(3), E27(2), D56(4), Q57, G142(2), S143(2), and Y191\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 20056441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eR14(2), D83(2), S86(2), Y88, T90, G142(2), P147(2), \u003cb\u003eD193(2)\u003c/b\u003e, and W222\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eW222\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eCID: 102074352\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-8.3\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eY13, R14, E27(3), D56(2), Y88, Q141(2), S143, and S146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eHuman IMPDH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSofosbuvir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eD274(2), S276(2), M325, G326, S327, G328, C331, D364(4), G415(2), K438, and G442\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRemdesivir\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eD274(4), S276(3), \u003cb\u003eR322\u003c/b\u003e, G324(2), M325(2), G326(2), S327, C331, D364(2), \u003cb\u003eM414\u003c/b\u003e, G415, K438(2), and \u003cb\u003eQ441\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eD274\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 99213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eS68(2)\u003c/b\u003e, D256(2), D274, S276, \u003cb\u003eR322\u003c/b\u003e, G326, C331, T333, and D364(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 194147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eS68\u003c/b\u003e, H93, D274(4), S275(2), S276, G326, S327, C331, T333, and D364(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCID: 20056441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eH93(2), N94, D256(2), R259, S276, \u003cb\u003eN303\u003c/b\u003e, G324(2), G326, S327, T333(2), and D364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eH93(3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eCID: 102074352\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-9.8\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT252(2), D256, S275(2), Q277, \u003cb\u003eN303\u003c/b\u003e, \u003cb\u003eR322\u003c/b\u003e, C331, T333, and D364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the interactions that established between Thuringiensin 6,3-lactone (CID: 102074352), and the SARS-CoV-2 RdRp (top left), R. \u003cem\u003eoryzae\u003c/em\u003e RdRp (top write), and the human IMPDH (down). This compound shows the best average binding affinities against the three proteins (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) compared to other nucleotide inhibitors. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e is represented by Discovery studio software, where the ligand is shown in the sticks, and the interacting residues are depicted in lines. The only type of interaction is the formation of H-bonds (dashed lines). Thuringiensin 6,3-lactone (CID: 102074352) formed 8 H-bonds to SARS-CoV-2 RdRp with residues K551, D618, D760, D761, W800, E811(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), and S814. For R. \u003cem\u003eoryzae\u003c/em\u003e RdRp Y13, R14, E27(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), D56(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), Y88, Q141(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), S143, and S146 formed 12 H-bonds with Thuringiensin 6,3-lactone. At the same time, residues T252(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), D256, S275(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), Q277, N303, R322, C331, T333, and D364 of the human IMPDH formed 11 H-bonds with Thuringiensin 6,3-lactone.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe current work reveals the favorable binding affinity of four adenosine derivatives against the SARS-CoV-2 RdRp, Rhizopus oryzae RdRp, and the human IMPDH. Thuringiensin 6,3-lactone has the best binding affinity to the three proteins, hence can be a potential inhibitor against COVID-19/Mucormycosis coinfection, while experimental validation is yet to be performed.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion:","content":"\u003cp\u003eRemdesivir proves its effectiveness against COVID-19 (reducing the hospitalization time). Four Thuringiensin derivatives (adenosine based) are tested against SARS-CoV-2 RdRp, Rhizopus \u003cem\u003eoryzae\u003c/em\u003e RdRp, and the human IMPDH using \u003cem\u003ein silico\u003c/em\u003e techniques. The results reveal the binding potential of the Thuringiensin derivatives against the viral, fungal, and human proteins. These adenosine derivatives can be potential inhibitors of the dual SARS-CoV-2 (COVID-19) R. oryzae (Mucormycosis) coinfection. Further, \u003cem\u003ein vitro\u003c/em\u003e and other experimental validations are suggested for the best compound (Thuringiensin 6,3-lactone) as future work.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors declare no conflict of interest in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contribution:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA.H.\u003c/strong\u003e own the idea, wrote the methods, and revised the manuscript. \u003cstrong\u003eA.E. \u0026amp; A.E.\u003c/strong\u003e drafted the manuscript, make calculations, and generated figures and tables. All the authors wrote and approved the final draft of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBibliotheca Alexandrina is used to performing the MDS calculations. This work is supported by the Cairo University COVID-19 fund received by \u003cstrong\u003eA.E.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWerthman-Ehrenreich A (2021) Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am J Emerg Med 42:264 e5\u0026ndash;e8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVaidyanathan G. Coronavirus variants are spreading in India\u0026mdash;what scientists know so far. Nature. 2021;332\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmud S, Elfiky AA, Amin A, Mohanto SC, Rahman E, Acharjee UK et al (2021) Targeting SARS-CoV-2 nonstructural protein 15 endoribonuclease: an in silico perspective. Future Virol 0(0):null\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElfiky AA, Ibrahim IM, Amin FG, Ismail AM, Elshemey WM (2021) COVID-19 and Cell Stress. 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Medicinal chemistry (Shariqah (United Arab Emirates)). 2019;15(2):130\u0026ndash;7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdem S, Eyupoglu V, Sarfraz I, Rasul A, Zahoor AF, Ali M et al (2021) Caffeic acid derivatives (CAFDs) as inhibitors of SARS-CoV-2: CAFDs-based functional foods as a potential alternative approach to combat COVID-19. Phytomedicine 85:153310\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":"Mucormycosis, SARS-CoV-2, computational drug design, Nucleotide inhibitors, RdRp, IMPDH","lastPublishedDoi":"10.21203/rs.3.rs-863321/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-863321/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMucormycosis has been reported in many regions associated with SARS-CoV-2 infections during the past few months. The viral RNA-dependent RNA polymerase (RdRp) is a crucial protein target in viral and fungal pathogens. Molecular docking combined with molecular dynamics simulation (MDS) is utilized to test nucleotide-based inhibitors against the RdRps of SARS-CoV-2 solved structure and Rhizopus \u003cem\u003eoryzae\u003c/em\u003e RdRp model built \u003cem\u003ein silico\u003c/em\u003e. Additionally, the human Inosine monophosphate dehydrogenase (IMPDH) was targeted by the same inhibitors. The results reveal a comparable binding affinity of four nucleotide derivatives compared to remdesivir and sofosbuvir against both IMPDH and the RdRps of SARS-CoV-2 and Rhizopus \u003cem\u003eoryzae\u003c/em\u003e, the main causing agent of mucormycosis. The binding affinities are calculated using different conformations of the RdRps after 100 ns MDS and trajectories clustering. The present study suggests the triple inhibition potential of four nucleotide inhibitors against SARS-CoV-2 \u0026amp; R. \u003cem\u003eoryzae\u003c/em\u003e RdRps and the human IMPDH, while experimental validation is yet to be performed. \u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Triple Targeting of Human IMPDH and Both RdRps of SARS-CoV-2 and Rhizopus Oryzae: An in Silico Perspective","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-09-03 21:45:39","doi":"10.21203/rs.3.rs-863321/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":"b3b3dad9-f633-4278-b19f-89689871a451","owner":[],"postedDate":"September 3rd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":6950914,"name":"Medicinal Chemistry"}],"tags":[],"updatedAt":"2021-09-03T21:46:01+00:00","versionOfRecord":[],"versionCreatedAt":"2021-09-03 21:45:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-863321","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-863321","identity":"rs-863321","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}