Molecular and Quantum Mechani̇cal Characteri̇zati̇on of Lawsone's Selecti̇ve Redox Tri̇AGİng: Atomi̇c Insi̇ghts İnto Anti̇-oxi̇dant Depri̇vati̇on and Induced Apoptosi̇s

Molecular and Quantum Mechani̇cal Characteri̇zati̇on of Lawsone's Selecti̇ve Redox Tri̇AGİng: Atomi̇c Insi̇ghts İnto Anti̇-oxi̇dant Depri̇vati̇on and Induced Apoptosi̇s | 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 Molecular and Quantum Mechani̇cal Characteri̇zati̇on of Lawsone's Selecti̇ve Redox Tri̇AGİng: Atomi̇c Insi̇ghts İnto Anti̇-oxi̇dant Depri̇vati̇on and Induced Apoptosi̇s Emin Zumrutdal This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9671473/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 Background: Lawsone (2-hydroxy-1,4-naphthoquinone) is a bioactive molecule with documented antitumoral, antimicrobial, and antithyroidal activities in previous in vivo studies. However, the quantum mechanical basis of its selective enzymatic modulation remains to be fully elucidated. Methods: Molecular docking simulations and high-precision Density Functional Theory (DFT) at the B3LYP/6-31G(d,p) level were employed to evaluate Lawsone’s interactions with key redox enzymes: NADPH oxidase (NOX), myeloperoxidase (MPO), lactoperoxidase (LPO), thyroid peroxidase (TPO), glucose-6-phosphate dehydrogenase (G6PD), glutathione peroxidase (GPx), and Catalase. Lawsone’s reactivity was analyzed comparatively against the natural substrate hydrogen peroxide ( H 2 O 2 ) and native ligands, including nicotinamide adenine dinucleotide phosphate (NADP + /NADPH) and oxidized glutathione (GSSG). Results: Docking results revealed that Lawsone exhibits competitive superiority over H 2 O 2 in peroxidase systems (MPO, LPO, TPO), with binding energies up to three times higher than the substrate (e.g., TPO: -6.003 vs. -2.182 kcal/mol). Positional analysis showed a ~3 Å advantage in G6PD and GPx active sites, suggesting a "kinetic hydrogen theft" that impairs antioxidant defenses. DFT analysis confirmed Lawsone’s high reactivity, evidenced by a narrow energy gap (ΔE gap : 3.276 eV) compared to H2O2 (8.030 eV). Notably, Lawsone does not create a significant inhibitory effect on the H 2 O 2 -producing enzyme NOX, allowing the continuation of production; however, it presents an "Oxidative Blockage" model by competitively affecting the enzymes in the clearance line (G6PD, GPx, Catalase). Conclusion: Our findings support a Selective Redox Triaging model, where Lawsone traps pathological cells within their own oxidative stress. This mechanism explains the anticancer, antimicrobial and antithyroidal effects observed in earlier experimental models and provides a molecular basis for clinical observations in G6PD-deficient scenarios. This study establishes a theoretical foundation for targeted pro-oxidant therapies at the subatomic level. Immunology Cell Survival and Cell Death Bioinformatics General Microbiology Toxicology Atomic and Molecular Physics Lawsone TPO Peroxidase NOX Molecular Docking DFT Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementTable1.docx SupplementTable2.docx SupplementFigure1.docx SupplementFigure2.docx SupplementFigure3.docx 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. 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Apoptosi̇s\u003c/strong\u003e\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"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":"Lawsone, TPO, Peroxidase, NOX, Molecular Docking, DFT","lastPublishedDoi":"10.21203/rs.3.rs-9671473/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9671473/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Lawsone (2-hydroxy-1,4-naphthoquinone) is a bioactive molecule with documented antitumoral, antimicrobial, and antithyroidal activities in previous \u003cem\u003ein vivo\u003c/em\u003e studies. However, the quantum mechanical basis of its selective enzymatic modulation remains to be fully elucidated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Molecular docking simulations and high-precision Density Functional Theory (DFT) at the B3LYP/6-31G(d,p) level were employed to evaluate Lawsone’s interactions with key redox enzymes: NADPH oxidase (NOX), myeloperoxidase (MPO), lactoperoxidase (LPO), thyroid peroxidase (TPO), glucose-6-phosphate dehydrogenase (G6PD), glutathione peroxidase (GPx), and Catalase. Lawsone’s reactivity was analyzed comparatively against the natural substrate hydrogen peroxide (\u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003eO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e) and native ligands, including nicotinamide adenine dinucleotide phosphate (NADP\u003csup\u003e+\u003c/sup\u003e/NADPH) and oxidized glutathione (GSSG).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Docking results revealed that Lawsone exhibits competitive superiority over \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003eO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e in peroxidase systems (MPO, LPO, TPO), with binding energies up to three times higher than the substrate (e.g., TPO: -6.003 vs. -2.182 kcal/mol). Positional analysis showed a ~3 Å advantage in G6PD and GPx active sites, suggesting a \"kinetic hydrogen theft\" that impairs antioxidant defenses. DFT analysis confirmed Lawsone’s high reactivity, evidenced by a narrow energy gap (ΔE\u003csub\u003e\u003cem\u003egap\u003c/em\u003e\u003c/sub\u003e: 3.276 eV) compared to H2O2 (8.030 eV). Notably, Lawsone does not create a significant inhibitory effect on the \u003cem\u003eH\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003eO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e-producing enzyme NOX, allowing the continuation of production; however, it presents an \"Oxidative Blockage\" model by competitively affecting the enzymes in the clearance line (G6PD, GPx, Catalase).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Our findings support a Selective Redox Triaging model, where Lawsone traps pathological cells within their own oxidative stress. This mechanism explains the anticancer, antimicrobial and antithyroidal effects observed in earlier experimental models and provides a molecular basis for clinical observations in G6PD-deficient scenarios. This study establishes a theoretical foundation for targeted pro-oxidant therapies at the subatomic level.\u003c/p\u003e","manuscriptTitle":"Molecular and Quantum Mechani̇cal Characteri̇zati̇on of Lawsone's Selecti̇ve Redox Tri̇AGİng: Atomi̇c Insi̇ghts İnto Anti̇-oxi̇dant Depri̇vati̇on and Induced Apoptosi̇s","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-12 02:42:40","doi":"10.21203/rs.3.rs-9671473/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":"6ee04adb-a3ff-4d07-b521-fc974d6a0912","owner":[],"postedDate":"May 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67969076,"name":"Immunology"},{"id":67969077,"name":"Cell Survival and Cell Death"},{"id":67969078,"name":"Bioinformatics"},{"id":67969079,"name":"General Microbiology"},{"id":67969080,"name":"Toxicology"},{"id":67969081,"name":"Atomic and Molecular Physics"}],"tags":[],"updatedAt":"2026-05-12T02:42:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-12 02:42:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9671473","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9671473","identity":"rs-9671473","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}