Mechanistic Insights into the Differential Efficacy of Sonratoclax against Venetoclax-Resistant BCL2 G101V

Resistant mechanisms to venetoclax, a selective BCL-2 inhibitor approved for hematological malignancies, are frequently mediated by the G101V mutation in BCL-2. Sonrotoclax illustrates superior potency against both wild-type and G101V-mutated BCL-2, yet the mechanistic basis remains unclear. This study employed computational methods to investigate the binding dynamics of both inhibitors. Structures were predicted with AlphaFold, refined via molecular dynamics simulations (MDS), and ligands were docked with AutoDock Vina. Four systems were subjected to triplicate 200 ns MDS, with analyses including RMSD, RMSF, buried surface area, protein-ligand interaction fingerprint, and MM/GBSA binding free energies. Results indicate venetoclax exhibits progressive dissociation from G101V BCL-2, with elevated RMSD, reduced buried surface area, and increased unbound states. In contrast, Sonrotoclax maintains a steady correlation, shows persistence with entropy-enthalpy compensation, displays negligible unbound time, higher binding free energies, and constant van der Waals anchors. Having all these results in mind, a “Dynamic Blockade” hypothesis is proposed, where Sonrotoclax’s flexibility enables sustained BH3 groove occupancy, blocking pro-apoptotic BH3-only proteins and overcoming allosteric perturbations induced by G101V. This mechanistic perspective proposes the optimal approach for designing resilient inhibitors to accelerate drug repurposing and development in oncology.