Singh, Ankit Kumar; Kumar, Adarsh; Singh, Harshwardhan; Martinović, Manuel; Pathak, Prateek; Mubashra, .; Shukla, Akanksha; Srivastava, Sameer; Verma, Amita; Novak, Jurica; Kumar, Pradeep (2025) Pyrimidin-4-bromobenzenesulfonamide/-4-nitrobenzenesulfonamide hybrids as potential BRAFV600E inhibitors: experimental, computational and biological evaluations. Journal of Computer-Aided Molecular Design, 39 (2). ISSN 0920-654X
![[img]](http://fulir.irb.hr/style/images/fileicons/application_pdf.png) |
PDF
- Accepted Version
- article
Restricted to Closed Access until 25 October 2026. Download (2MB) | Request a personal copy from author |
Abstract
BRAF mutations were first discovered by Davies et al. in 2002. BRAFV600E mutation is the most prevalent, accounting for approximately 90% of all BRAF mutations. BRAFV600E mutations have been identified at varying frequencies across multiple human cancers, including malignant melanoma (70–90%), thyroid cancer (45–50%), colorectal cancer (5–20%), and others. In this study, we designed a series of pyrimidine-sulfonamide hybrids, inspired by first- and second-generation FDA-approved BRAF inhibitors such as sorafenib, dabrafenib, and vemurafenib. The designed compounds were intended to target the αC-OUT/DFG-IN conformation of the BRAFV600E mutant protein. Eighteen compounds (B1–B18) were synthesized and characterized using spectral techniques. Molecular docking and MD simulations were carried out to assess their binding affinity and stability with the BRAFV600E protein. Kinase inhibition was assessed using a BRAFV600E specific assay, and anticancer activity was tested against HCT-116, A375, HT-29, and TPC-1 cell lines. Among the tested derivatives, B14 exhibited the highest cytotoxicity against HCT-116, B8 was most effective against A375, B18 showed potent inhibition in HT-29, and B3 demonstrated the strongest activity in TPC-1 cells. All four compounds exhibited activity comparable to sorafenib. Notably, B4 emerged as the most potent BRAFV600E kinase inhibitor in assays.
| Item Type: | Article | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Uncontrolled Keywords: | BRAFV600E; Pyrimidine-sulfonamide; Anticancer; Molecular docking; Molecular Dynamics simulation; Sorafenib | ||||||||
| Subjects: | NATURAL SCIENCES NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Physical Chemistry NATURAL SCIENCES > Chemistry > Theoretical Chemistry NATURAL SCIENCES > Chemistry > Organic Chemistry BIOMEDICINE AND HEALTHCARE BIOMEDICINE AND HEALTHCARE > Pharmacy BIOMEDICINE AND HEALTHCARE > Pharmacy > Medical Biochemistry |
||||||||
| Divisions: | Center for Informatics and Computing | ||||||||
| Projects: |
|
||||||||
| Depositing User: | Jurica Novak | ||||||||
| Date Deposited: | 14 Jan 2026 09:49 | ||||||||
| URI: | http://fulir.irb.hr/id/eprint/10781 | ||||||||
| DOI: | 10.1007/s10822-025-00690-5 |
Actions (login required)
 |
View Item |
Altmetric
Altmetric
