Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAFV600E inhibitors
AuthorsSingh, Ankit Kumar
Yadav, Jagat Pal
Poulson, Benjamin Gabriel
Emwas, Abdul-Hamid M.
KAUST DepartmentBiological and Environmental Science and Engineering (BESE) Division
Red Sea Research Center (RSRC)
Permanent link to this recordhttp://hdl.handle.net/10754/685065
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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 (αC-IN/DFG-IN), type II (αC-IN/DFG-OUT), type I1/2 (αC-OUT/DFG-IN), and type I/II (αC-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 [αC-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.
CitationSingh, A. K., Novak, J., Kumar, A., Singh, H., Thareja, S., Pathak, P., Grishina, M., Verma, A., Yadav, J. P., Khalilullah, H., Pathania, V., Nandanwar, H., Jaremko, M., Emwas, A.-H., & Kumar, P. (2022). Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAFV600E inhibitors. RSC Advances, 12(46), 30181–30200. https://doi.org/10.1039/d2ra05751d
SponsorsThe APC was funded by King Abdullah University of Science and Technology (KAUST), Thuwal, Jeddah, Saudi Arabia. Authors are thankful to Central University of Punjab, Bathinda, DST-FIST, India; Isabella cluster of the University Computing Center, University of Zagreb, Croatia; South Ural State University, Chelyabinsk, Russia; for providing the necessary facilities to execute this research. Dr Prateek Pathak and Dr Maria Grishina also acknowledged that their part of the work was supported by Ministry of Science and Higher Education of Russia (Grant FENU-2020-0019).
PublisherRoyal Society of Chemistry (RSC)
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