Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAFV600E inhibitors

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dc.contributor.authorSingh, Ankit Kumar
dc.contributor.authorNovak, Jurica
dc.contributor.authorKumar, Adarsh
dc.contributor.authorSingh, Harshwardhan
dc.contributor.authorThareja, Suresh
dc.contributor.authorPathak, Prateek
dc.contributor.authorGrishina, Maria
dc.contributor.authorVerma, Amita
dc.contributor.authorYadav, Jagat Pal
dc.contributor.authorKhalilullah, Habibullah
dc.contributor.authorPathania, Vikas
dc.contributor.authorNandanwar, Hemraj
dc.contributor.authorJaremko, Mariusz
dc.contributor.authorEmwas, Abdul-Hamid
dc.contributor.authorKumar, Pradeep
dc.date.accessioned2024-01-21T10:38:27Z
dc.date.accessioned2024-08-13T12:05:24Z
dc.date.available2024-01-21T10:38:27Z
dc.date.available2024-08-13T12:05:24Z
dc.date.issued2022-10-21T00:00:00
dc.description.abstractThe �RAS-RAF-MEK-ERK� pathway is an important signaling pathway in melanoma. BRAFV600E (70-90%) is the most common mutation in this pathway. BRAF inhibitors have four types of conformers: type I (?C-IN/DFG-IN), type II (?C-IN/DFG-OUT), type I1/2 (?C-OUT/DFG-IN), and type I/II (?C-OUT/DFG-OUT). First- and second-generation BRAF inhibitors show resistance to BRAFV600E and are ineffective against malignancies induced by dimer BRAF mutants causing �paradoxical� activation. In the present study, we performed molecular modeling of pyrimidine-sulfonamide hybrids inhibitors using 3D-QSAR, molecular docking, and molecular dynamics simulations. Previous reports reveal the importance of pyrimidine and sulfonamide moieties in the development of BRAFV600E inhibitors. Analysis of 3D-QSAR models provided novel pyrimidine sulfonamide hybrid BRAFV600E inhibitors. The designed compounds share similarities with several structural moieties present in first- and second-generation BRAF inhibitors. A total library of 88 designed compounds was generated and molecular docking studies were performed with them. Four molecules (T109, T183, T160, and T126) were identified as hits and selected for detailed studies. Molecular dynamics simulations were performed at 900 ns and binding was calculated. Based on molecular docking and simulation studies, it was found that the designed compounds have better interactions with the core active site [the nucleotide (ADP or ATP) binding site, DFG motif, and the phospho-acceptor site (activation segment) of BRAFV600E protein than previous inhibitors. Similar to the FDA-approved BRAFV600E inhibitors the developed compounds have [?C-OUT/DFG-IN] conformation. Compounds T126, T160 and T183 interacted with DIF (Leu505), making them potentially useful against BRAFV600E resistance and malignancies induced by dimer BRAF mutants. The synthesis and biological evaluation of the designed molecules is in progress, which may lead to some potent BRAFV600E selective inhibitors. � 2022 The Royal Society of Chemistry.en_US
dc.identifier.doi10.1039/d2ra05751d
dc.identifier.issn20462069
dc.identifier.urihttp://10.2.3.109/handle/32116/3574
dc.identifier.urlhttp://xlink.rsc.org/?DOI=D2RA05751D
dc.language.isoen_USen_US
dc.publisherRoyal Society of Chemistryen_US
dc.subjectAromatic compoundsen_US
dc.subjectChemical activationen_US
dc.subjectComputational chemistryen_US
dc.subjectMolecular dynamicsen_US
dc.subjectMolecular modelingen_US
dc.subjectMoleculesen_US
dc.subjectSulfur compoundsen_US
dc.subjectSynthesis (chemical)en_US
dc.subject3D-QSARen_US
dc.subjectDocking studiesen_US
dc.subjectDynamics simulationen_US
dc.subjectGaussian fielden_US
dc.subjectMolecular dockingen_US
dc.subjectMolecular simulationsen_US
dc.subjectSecond generationen_US
dc.subjectSignalling pathwaysen_US
dc.subjectSimulation studiesen_US
dc.subjectSulphonamidesen_US
dc.subjectDimersen_US
dc.titleGaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAFV600E inhibitorsen_US
dc.title.journalRSC Advancesen_US
dc.typeArticleen_US
dc.type.accesstypeOpen Accessen_US

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