N-heterocycle-containing sulfonamides as potential inhibitors of the cancer-related Vps34 enzyme: A theoretical study

Abstract

This work provides a theoretical assessment of 30 N-heterocycle-bearing sulfonamide derivatives as prospective inhibitors of the cancer-associated enzyme Vps34, a central regulator of autophagy and tumour development. Molecular docking simulations carried out with AutoDock Vina ranked the compounds by binding affinity, grouping them into weak, moderate, and strong binders. Six derivatives (8, 12, 13, 14, 18, 30) displayed the most favourable interactions with key active-site residues such as phenylalanine PHE612, isoleucine ILE634, tyrosine TYR670, leucine LEU750, ILE760, lysine LYS636. These leading candidates were subsequently evaluated for druglikeness using Lipinski’s Rule of Five and oral bioavailability via SwissADME radar plots, all of which indicated suitable profiles. Complementary ADMET predictions from Deep-PK supported acceptable pharmacokinetic behaviour and manageable safety risks. Furthermore, molecular dynamics simulation were also carried out to gain insights into the interactions between Vps34 and compound 30. Throughout the studies, compound 30 emerged as the most promising lead, combining strong binding affinity with favourable physicochemical features, high predicted oral bioavailability, and favourable protein interaction profile. Accordingly, additional in vitro and in vivo investigations are needed to fully establish the therapeutic potential of sulfonamide scaffolds, especially compound 30, as Vps34-targeted anticancer agents.