The impact of Thr91 mutation on c-Src resistance to UM-164: molecular dynamics study revealed a new opportunity for drug design.

摘要: The emergence of a drug resistant non-receptor tyrosine kinase (c-Src) in triple-negative breast cancer (TNBC) remains prime concern relation to the burden TNBC among people living with and development. Thr91 mutation was found induce complete loss protein conformation required for fitness. Herein, we provide first account molecular impact on c-Src resistance experimental UM-164 using various computational approaches, namely dynamics simulation, principal component analysis (PCA), dynamic cross-correlation matrices (DCCM) analysis, hydrogen bond occupancy, thermodynamics calculation, ligand-residue interaction residue networks (RINs). Findings from this study revealed that leads steric conflict between side chain methionine (Met91); distorts optimum orientation conformational space mutant compared wild-type; decreases formation residues structure; binding energy by -13.416 kcal mol-1; reduces correlation induces change overall structure an inactive active conformation; ligand atomic network network. This report provides important insights will assist further design novel dual inhibitors minimise chances triple negative cancer.