Multi-reference poly-conformational computational methods for de-novo design, optimization, and repositioning of pharmaceutical compounds

Multi-reference poly-conformational computational methods for de-novo design, optimization, and repositioning of pharmaceutical compounds | 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 Multi-reference poly-conformational computational methods for de-novo design, optimization, and repositioning of pharmaceutical compounds Vadim Alexandrov, Alexander Kirpich, Yuriy Gankin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-120450/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 The COVID-19 epidemic, SARS-CoV-2, that began in December of 2019 has drastically altered the aspects of daily life across the global society. Time-effective treatment of those infected has since become a major goal with multiple treatment strategies having been designed to prevent the progression of the disease into severe pneumonia. To date, no drug has been found to be 100% effective against SARS-COV-2, possibly because each candidate drug was targeting only one particular mechanism of action (MoA). Neither proposed up-to-date anti-SARS-COV-2 vaccine are 100% effective. To contribute to the process of finding a more robust small-molecule solution, utilizing several anti-SARS-COV-2 MoAs, a novel framework is presented; where the in silico generated set of virtual library compounds is compared to six known reference drugs: Chloroquine, Favipiravir, Remdesivir, JQ1, Apicidine, and Haloperidol which have been already used for SARS-CoV-2 treatment. The aims were: a) to present a universal search framework for potential candidate compounds based on the comparison of multiple similarities between compounds’ conformers and b) to identify candidate compounds that are simultaneously “close” to each of the six known reference compounds that counteract SARS-CoV-2 via different mechanisms of action. General Biochemistry Other Public Policy COVID-19 conformers multi-reference poly-conformational in silico ligand-based structure-based SARS-COV-2 fingerprints cheminformatics similarity virtual library computational framework Figures Figure 1 Figure 2 Full Text 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. 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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-120450","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":5726319,"identity":"28c52857-5ccd-4471-8e0d-d2542e952d76","order_by":0,"name":"Vadim Alexandrov","email":"","orcid":"https://orcid.org/0000-0002-0254-9799","institution":"Liquid Algo LLC","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vadim","middleName":"","lastName":"Alexandrov","suffix":""},{"id":5726320,"identity":"3b3055ad-bf6c-427a-90c0-b9792f10c38c","order_by":1,"name":"Alexander Kirpich","email":"","orcid":"https://orcid.org/0000-0001-5486-0338","institution":"Georgia State University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Kirpich","suffix":""},{"id":5726321,"identity":"1a65e5cb-e887-4d61-8907-a2755d435881","order_by":2,"name":"Yuriy Gankin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYJCCA2CSh7GB4QNMKIFYLYwzQAw2IrRAAA8DAzMPTAs+YHAj9+FhHoZaeXOew22PbcoOy5vLNx/78IDBTk63AZeWdAOgluOGO3sb241zzh023NnGljwjgSHZ2OwALi1pDEAtxxg3nGdsk85tO8y44RiPMdAvBxK3EdBiD9Zi2XbYnlgtNYkbzja2STO2HU4kqEXyzDOGg3MMDiRvOHOwTbLnXHryhmNpyQwJBrj9wnc8jfnDm4o62w1n0p9J/Ciztt1w+PBhxh8VdnK4tCgAxZl4DA5DufA4McCuHATkGxgYGH8w1KFrGQWjYBSMglGAAACiBGHJNeyruwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-0046-1037","institution":"Quantori","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yuriy","middleName":"","lastName":"Gankin","suffix":""}],"badges":[],"createdAt":"2020-12-02 16:16:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-120450/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-120450/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":4024972,"identity":"ccd9b246-e597-4be3-aa15-2b68b2451847","added_by":"auto","created_at":"2020-12-04 17:43:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1709092,"visible":true,"origin":"","legend":"The compounds presented in panels A and B from the antiviral Enamine virtual sub-library collection that were found to maximize conformer overlap scores with the six reference compounds. In addition to that sulphonyl bridge in panel B (circled in red) is a signature of the classic antiviral compounds (e.g. well-known drug sulfapyridine), as well as the ether bond. The bridge allows for 3D flexibility for the molecule to change conformation and bind to multiple targets.","description":"","filename":"Figure01ver2.png","url":"https://assets-eu.researchsquare.com/files/rs-120450/v1/a80b7c713bff0f9f237386b8.png"},{"id":4024973,"identity":"c1ff1b7c-0e9d-435e-a34e-89c5df297fa6","added_by":"auto","created_at":"2020-12-04 17:43:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":368326,"visible":true,"origin":"","legend":"The original chloroquine is presented in panel A, while the chloroquine analogs optimized in the modify-score-select algorithm are presented in panels B and C.","description":"","filename":"Figure02ver2.png","url":"https://assets-eu.researchsquare.com/files/rs-120450/v1/5d69572b9ed3e005f5b0d13c.png"},{"id":13562397,"identity":"cc114ba1-ad8e-4536-a674-ed3055334482","added_by":"auto","created_at":"2021-09-17 03:12:55","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":424318,"visible":true,"origin":"","legend":"","description":"","filename":"MultiObjParadigmaPaperfinalnov2717.58nofigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-120450/v1_covered.pdf"},{"id":4024974,"identity":"742d2fc5-414b-45c9-81e5-03d585adce42","added_by":"auto","created_at":"2020-12-04 17:43:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":599249,"visible":true,"origin":"","legend":"","description":"","filename":"MultiObjParadigmaPaperfinalnov2717.58nofigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-120450/v1_stamped.pdf"}],"financialInterests":"","formattedTitle":"Multi-reference poly-conformational computational methods for de-novo design, optimization, and repositioning of pharmaceutical compounds","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-120450/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"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":"COVID-19, conformers, multi-reference, poly-conformational, in silico, ligand-based, structure-based, SARS-COV-2, fingerprints, cheminformatics, similarity, virtual library, computational framework","lastPublishedDoi":"10.21203/rs.3.rs-120450/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-120450/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe COVID-19 epidemic, SARS-CoV-2, that began in December of 2019 has drastically altered the aspects of daily life across the global society. Time-effective treatment of those infected has since become a major goal with multiple treatment strategies having been designed to prevent the progression of the disease into severe pneumonia. To date, no drug has been found to be 100% effective against SARS-COV-2, possibly because each candidate drug was targeting only one particular mechanism of action (MoA). Neither proposed up-to-date anti-SARS-COV-2 vaccine are 100% effective. To contribute to the process of finding a more robust small-molecule solution, utilizing several anti-SARS-COV-2 MoAs, a novel framework is presented; where the in silico generated set of virtual library compounds is compared to six known reference drugs: Chloroquine, Favipiravir, Remdesivir, JQ1, Apicidine, and Haloperidol which have been already used for SARS-CoV-2 treatment. The aims were: a) to present a universal search framework for potential candidate compounds based on the comparison of multiple similarities between compounds\u0026rsquo; conformers and b) to identify candidate compounds that are simultaneously \u0026ldquo;close\u0026rdquo; to each of the six known reference compounds that counteract SARS-CoV-2 via different mechanisms of action.\u003c/p\u003e","manuscriptTitle":"Multi-reference poly-conformational computational methods for de-novo design, optimization, and repositioning of pharmaceutical compounds","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-04 17:43:50","doi":"10.21203/rs.3.rs-120450/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":"841b9558-7be2-49ee-a401-a0c93ad58b03","owner":[],"postedDate":"December 4th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":1328285,"name":"General Biochemistry"},{"id":1328286,"name":"Other Public Policy"}],"tags":[],"updatedAt":"2021-02-03T05:59:12+00:00","versionOfRecord":[],"versionCreatedAt":"2020-12-04 17:43:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-120450","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-120450","identity":"rs-120450","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}