{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T22:39:00Z","timestamp":1772663940680,"version":"3.50.1"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001410","name":"Human Resource Development Group","doi-asserted-by":"publisher","award":["27\/0368\/20 EMR-II"],"award-info":[{"award-number":["27\/0368\/20 EMR-II"]}],"id":[{"id":"10.13039\/501100001410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Mitogen-activated protein kinase 1 (MAPK1) is a serine\/threonine kinase that plays a crucial role in the MAP kinase signaling transduction pathway. This pathway plays a crucial role in various cellular processes, including cell proliferation, differentiation, adhesion, migration, and survival. Besides, many chemotherapeutic drugs targeting the MAPK pathway are used in clinical practice, and novel inhibitors of MAPK1 with improved specificity and efficacy are required. Hence, targeting MAPK1 can be crucial to control metastasis in cancer therapeutics. In this study, we utilized a structure-guided virtual screening approach to screen a library of thousands of natural compounds from the ZINC database. The Lipinski rule of five (RO5) was used as a criterion for the primary selection of natural compounds. The screened compounds were prioritized based on their binding affinity, docking scores, and specificity towards the kinase domain of MAPK1 during the molecular docking process. Subsequently, the selected hits underwent rigorous screening that included the identification of potential pan-assay interference compounds (PAINS), ADMET evaluation, and prediction of pharmacological activities using PASS analysis. Afterwards, we performed a comprehensive interaction analysis to explore the binding prototypes of the screened molecules with the key residues within the MAPK1 kinase domain. Finally, selected molecules underwent extensive all-atom molecular dynamics (MD) simulations for a time duration of 200 nanoseconds. The study pinpointed three natural compounds with ZINC database IDs ZINC0209285, ZINC02130647, and ZINC02133691 as potential inhibitors of MAPK1. The study highlights that these compounds could be explored further in preclinical and clinical investigations to develop anticancer therapeutics.<\/jats:p>","DOI":"10.1371\/journal.pone.0311954","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T18:36:27Z","timestamp":1737743787000},"page":"e0311954","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics"],"prefix":"10.1371","volume":"20","author":[{"given":"Md Nayab","family":"Sulaimani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shazia","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farah","family":"Anjum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taj","family":"Mohammad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anas","family":"Shamsi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0602-3719","authenticated-orcid":true,"given":"Ravins","family":"Dohare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-4940","authenticated-orcid":true,"given":"Md. 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Parmar","year":"2022","journal-title":"Biointerface Res Appl Chem"},{"key":"pone.0311954.ref032","doi-asserted-by":"crossref","first-page":"130941","DOI":"10.1016\/j.molstruc.2021.130941","article-title":"Identification of anti-mycobacterial agents against mmpL3: virtual screening, ADMET analysis and MD simulations","volume":"1244","author":"KA Bhakhar","year":"2021","journal-title":"Journal of Molecular Structure"},{"key":"pone.0311954.ref033","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1007\/s10593-014-1496-1","article-title":"Prediction of the biological activity spectra of organic compounds using the PASS online web resource","volume":"50","author":"D Filimonov","year":"2014","journal-title":"Chemistry of Heterocyclic Compounds"},{"key":"pone.0311954.ref034","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1007\/s11172-017-1954-x","article-title":"Computational platform Way2Drug: from the prediction of biological activity to drug 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Alam","year":"2022"},{"issue":"10","key":"pone.0311954.ref047","doi-asserted-by":"crossref","first-page":"e0258929","DOI":"10.1371\/journal.pone.0258929","article-title":"Investigating single amino acid substitutions in PIM1 kinase: A structural genomics approach","volume":"16","author":"A Shafie","year":"2021","journal-title":"Plos one"},{"issue":"42","key":"pone.0311954.ref048","doi-asserted-by":"crossref","first-page":"12315","DOI":"10.1021\/jp208585r","article-title":"The free energy landscape analysis of protein (FIP35) folding dynamics.","volume":"115","author":"SV Krivov","year":"2011","journal-title":"The journal of physical chemistry B."},{"issue":"4","key":"pone.0311954.ref049","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1021\/acs.jpcb.6b11696","article-title":"Free-energy landscape of protein\u2013ligand interactions coupled with protein structural changes","volume":"121","author":"K Moritsugu","year":"2017","journal-title":"The Journal of Physical Chemistry 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