Finally, the total binding free energy (TBE) calculations revealed that ARQ531 exhibits broadly conserved binding energetics across clinically observed BTK mutants, with select variants (notably C481 substitutions) showing moderately enhanced stabilization relative to the wild type. These findings confirm that ARQ 531 remains a significant investigational therapy specifically for overcoming drug resistance in multiple leukemias and B-cell malignancies and can serve as a starting point for designing more robust and effective BTK inhibitors.