{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T06:02:49Z","timestamp":1784872969773,"version":"3.55.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The TP53 mutations in Non-Small Cell Lung Cancer (NSCLC) remain a formidable clinical challenge. Current strategies, using the covalent binder APR-246, are limited by off-target toxicity and resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study screens 1,580\n                      <jats:italic>Bacillus<\/jats:italic>\n                      -derived metabolites to identify novel non-covalent pharmacological chaperones for native, conformational (R175H), and contact (R273H) p53 mutants. Virtual screening, ADMET profiling, molecular docking, extended 500 ns Molecular Dynamics (MD) simulations and Principal Component Analysis, against experimental anti-cancer drug APR-246, and top hit compounds.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Hydroxymycotrienin A emerged as the potential candidate, demonstrating thermodynamic superiority with binding affinities of \u22126.63 kcal\/mol (R175H) and \u22126.57 kcal\/mol (R273H), demonstrated significant superior non covalent docking affinity compared to APR-246 parent scaffold (approximately \u22123.5 kcal\/mol) in the mutated p53 protein, suggesting a direct pharmacological chaperone activity. Unlike the covalent alkylating mechanism of APR-246, Hydroxymycotrienin A utilizes a non-covalent network to chaperone the mutant p53. MD simulations revealed that Hydroxymycotrienin A acted as a structural stabilizer for the conformational mutant R175H by suppressing atomic fluctuations within the L2 loop and reducing overall structural deviations. In the contact mutant R273H, the ligand stabilized the DNA-binding interface while maintaining favorable conformational dynamics without introducing steric clashes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      ADMET profiling predicts high bioavailability and a non-toxic safety profile, characterizing Hydroxymycotrienin A as a promising, bioavailable \u2018privileged scaffold\u2019 that offers a non-covalent therapeutic strategy for NSCLC. By restoring p53 function, this study addresses Sustainable Development Goals Target 3.4 to reduce premature mortality from non-communicable diseases. However, future\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies are required to validate the efficacy of these compounds.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fbinf.2026.1875897","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:35:55Z","timestamp":1784871355000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional restoration of conformational (R175H) and contact (R273H) mutant p53 by Bacillus-derived Hydroxymycotrienin A in non-small cell lung cancer: a computational approach"],"prefix":"10.3389","volume":"6","author":[{"given":"Adeline Celina","family":"Rufus","sequence":"first","affiliation":[{"name":"Medical Probiotics Lab, Department of Biotechnology, Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education & Research","place":["Chennai, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidharth","family":"Kumar N","sequence":"additional","affiliation":[{"name":"Computational Biology Lab, Department of Biotechnology, Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education & Research","place":["Chennai, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magesh","family":"Ramasamy","sequence":"additional","affiliation":[{"name":"Computational Biology Lab, Department of Biotechnology, Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education & Research","place":["Chennai, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elavarashi","family":"Elangovan","sequence":"additional","affiliation":[{"name":"Medical Probiotics Lab, Department of Biotechnology, Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education & Research","place":["Chennai, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e01550","DOI":"10.1002\/adts.202501550","article-title":"DrLungker: a deep ensemble learning framework for predicting anti\u2010lung cancer compound activity and validating multitarget potency through WaterMap, DFT, MD simulations, and MM\u2010GBSA analysis","volume":"9","author":"Ahmad","year":"2026","journal-title":"Adv. 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