Virtual screening, structure based pharmacophore mapping, and molecular simulation studies of pyrido[2,3-d]pyrimidines as selective thymidylate synthase inhibitors

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dc.contributor.authorKumar, Adarsh
dc.contributor.authorNovak, Jurica
dc.contributor.authorSingh, Ankit Kumar
dc.contributor.authorSingh, Harshwardhan
dc.contributor.authorThareja, Suresh
dc.contributor.authorPathak, Prateek
dc.contributor.authorGrishina, Maria
dc.contributor.authorVerma, Amita
dc.contributor.authorKumar, Pradeep
dc.date.accessioned2024-01-21T10:38:34Z
dc.date.accessioned2024-08-13T12:05:30Z
dc.date.available2024-01-21T10:38:34Z
dc.date.available2024-08-13T12:05:30Z
dc.date.issued2023-05-08T00:00:00
dc.description.abstractHuman thymidylate synthase is the rate-limiting enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate. dUMP (pyrimidine) and folate binding site hTS inhibitors showed resistance in colorectal cancer (CRC). In the present study, we have performed virtual screening of the pyrido[2,3-d]pyrimidine database, followed by binding free energy calculations, and pharmacophore mapping to design novel pyrido[2,3-d]pyrimidine derivatives to stabilize inactive confirmation of hTS. A library of 42 molecules was designed. Based on the molecular docking studies, four ligands (T36, T39, T40, and T13) were identified to have better interactions and docking scores with the catalytic sites [dUMP (pyrimidine) and folate binding sites] of hTS protein than standard drug, raltitrexed. To validate efficacy of the designed molecules, we performed molecular dynamics simulation studies at 1000 ns with principal component analysis and binding free energy calculations on the hTS protein, also drug likeness properties of all hits were in acceptable range. Compounds T36, T39, T40, and T13 interacted with the catalytic amino acid (Cys195), an essential amino acid for anticancer activity. The designed molecules stabilized the inactive conformation of hTS, resulting in the inhibition of hTS. The designed compounds will undergo synthesis and biological evaluation, which may yield selective, less toxic, and highly potent hTS inhibitors. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.en_US
dc.identifier.doi10.1080/07391102.2023.2208205
dc.identifier.issn7391102
dc.identifier.urihttp://10.2.3.109/handle/32116/3603
dc.identifier.urlhttps://www.tandfonline.com/doi/full/10.1080/07391102.2023.2208205
dc.language.isoen_USen_US
dc.publisherTaylor and Francis Ltd.en_US
dc.subjectchemoresistanceen_US
dc.subjectcolorectal canceren_US
dc.subjectconformationsen_US
dc.subjectHuman thymidylate synthaseen_US
dc.subjectmolecular simulationen_US
dc.titleVirtual screening, structure based pharmacophore mapping, and molecular simulation studies of pyrido[2,3-d]pyrimidines as selective thymidylate synthase inhibitorsen_US
dc.title.journalJournal of Biomolecular Structure and Dynamicsen_US
dc.typeArticleen_US
dc.type.accesstypeClosed Accessen_US

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