Singh, Ankit Kumar; Kumar, Adarsh; Singh, Harshwardhan; Pathak, Prateek; Verma, Amita; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Novak, Jurica; Kumar, Pradeep (2025) Targeted design, synthesis, molecular dynamics, ADME and in –vitro anticancer assessment of oxo-tetrahydro-pyrimidin-benzenesulfonamide hybrids as potential BRAFV600E inhibitors. Scientific Reports, 15 (1). ISSN 2045-2322
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Abstract
BRAF mutations appear to varying degrees in human cancers. Proposed oxo-tetrahydro-pyrimidin-benzenesulfonamide hybrids target [αC-OUT/DFG-IN] conformation of BRAFV600Esimilar to second-generation FDA-approved drugs. Nine compounds (S1–S9) were synthesized and spectrally characterized using Mass, HRMS,1H, and13C NMR. All synthesized derivatives were tested for anti-proliferative activity against two cancer cell lines, and the percentage of BRAFV600E enzyme kinase inhibition was calculated using sorafenib as the standard. Molecular docking was performed for all compounds, while molecular dynamics simulations were conducted for the most active molecules, providing insights into their stability and interactions within the target binding site. The biological assay revealed that most compounds exhibited significant anticancer activity, with compound S4 demonstrating strong inhibition of the BRAFV600E kinase. Notably, S4 (91%) and S1 (87%) showed potent inhibitory effects, comparable to the reference drug, sorafenib (94%). Based on these promising results, S4 and S1 were selected for molecular dynamics simulations to elucidate their binding stability and conformational dynamics within the BRAFV600E active site. These findings highlight that these compounds may act as potential lead compounds for the development of BRAFV600E inhibitors.
| Item Type: | Article | ||||||||
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| Uncontrolled Keywords: | BRAFV600E; Urea; Pyrimidin-benzenesulfonamide; Computational; Molecular dynamics; Anticancer | ||||||||
| Subjects: | NATURAL SCIENCES > Chemistry | ||||||||
| Divisions: | Center for Informatics and Computing | ||||||||
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| Depositing User: | Jurica Novak | ||||||||
| Date Deposited: | 13 Oct 2025 08:02 | ||||||||
| URI: | http://fulir.irb.hr/id/eprint/10068 | ||||||||
| DOI: | 10.1038/s41598-025-18835-9 |
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