Insights into the structure-activity relationship of pyrimidine-sulfonamide analogues for targeting BRAF V600E protein

Abstract

B-rapidly accelerated fibrosarcoma (BRAF) V600E plays a crucial role in the progression of cutaneous melanoma. Core structures of BRAF V600E inhibitors are based on pyrimidine-sulfonamide scaffolds. Exploring the QSAR of these structures can improve our understanding of BRAF V600E inhibitor drug design. This study utilized machine learning-based QSAR to elucidate chemical substructures of pyrimidine-sulfonamide analogues that correlated to the BRAF V600E inhibitory activity. The findings indicate that the support vector regression (SVR) combined with 15 fingerprints achieved the highest statistical performances in terms of goodness-of-fit, robustness, and predictability. Nine key fingerprints from pyrimidine-sulfonamide analogues were identified to exert the BRAF V600E inhibitory activity. These key fingerprints were validated using network-based activity cliff landscape and molecular docking. Together, the developed algorithm can serve as a screening tool for designing BRAF V600E inhibitors. To further utilize this model, we deployed our developed algorithm at https://qsarlabs.com/#braf.