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HPC Accelerated Discovery of Next-Generation BRAFV600E Inhibitors for Cancer Therapy

Published paper in "Journal of Computer-Aided Molecular Design": "Pyrimidin-4-bromobenzenesulfonamide/-4-nitrobenzenesulfonamide hybrids as potential BRAFV600E inhibitors: experimental, computational and biological evaluations"
Oct 28th 2025
HPC Accelerated Discovery of Next-Generation BRAFV600E Inhibitors for Cancer Therapy

Targeting BRAFV600E with the Power of HPC

The BRAFV600E mutation is one of the most clinically significant oncogenic drivers, appearing in cancers such as melanoma, thyroid cancer, and colorectal cancer. To address this, we designed a new series of pyrimidine–sulfonamide hybrid molecules, inspired by FDA-approved BRAF inhibitors (sorafenib, dabrafenib, and vemurafenib).

Using high-performance computing (HPC), we performed molecular docking and all-atom molecular dynamics simulations to evaluate how these compounds interact with the BRAFV600E protein in its αC-OUT/DFG-IN conformation. A total of 18 compounds (B1–B18) were synthesized and characterized.

We then assessed:

  • BRAFV600E kinase inhibition
  • Anticancer activity across HCT-116, A375, HT-29, and TPC-1 cell lines

Key findings:

  • B14 showed strong cytotoxicity against HCT-116
  • B8 was most effective against A375
  • B18 showed potent inhibition in HT-29
  • B3 demonstrated the strongest effect in TPC-1
  • All four matched the performance of sorafenib
  • B4 emerged as the most potent BRAFV600E kinase inhibitor

Why this matters:
This work demonstrates how supercomputing accelerates rational drug design, helping identify promising therapeutic candidates more efficiently and at lower cost.

Read the paper:: https://doi.org/10.1007/s10822-025-00690-5

Title: Pyrimidin-4-bromobenzenesulfonamide/-4-nitrobenzenesulfonamide hybrids as potential BRAFV600E inhibitors: experimental, computational and biological evaluations

Research supported by the Croatian Science Foundation (IP-2022-4658) and powered by the Supek supercomputer at SRCE, University of Zagreb.