QSAR modeling and in silico design of small-molecule inhibitors targeting the interaction between E3 ligase VHL and HIF-1 $$\alpha $$ α

Protein-protein interactions (PPIs) have attracted much attention recently because of their preponderant role in most biological processes. The prevention of the interaction between E3 ligase VHL and HIF-1[Formula: see text] may improve tolerance to hypoxia and ameliorate the prognosis of many diseases. To obtain novel potent inhibitors of VHL/HIF-1[Formula: see text] interaction, a series of hydroxyproline-based inhibitors were investigated for structural optimization using a combination of QSAR modeling and molecular docking. Here, 2D- and 3D-QSAR models were developed by genetic function approximation (GFA) and comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods, respectively. The top-ranked models with strict validation revealed satisfactory statistical parameters (CoMFA with [Formula: see text], 0.637; [Formula: see text], 0.955; [Formula: see text], 0.944; CoMSIA with [Formula: see text], 0.649; [Formula: see text], 0.954; [Formula: see text], 0.911; GFA with [Formula: see text], 0.721; [Formula: see text], 0.801; [Formula: see text], 0.861). The selected five 2D-QSAR descriptors were in good accordance with the 3D-QSAR results, and contour maps gave the visualization of feature requirements for inhibitory activity. A new diverse molecular database was created by molecular fragment replacement and BREED techniques for subsequent virtual screening. Eventually, 31 novel hydroxyproline derivatives stood out as potential VHL/HIF-1[Formula: see text] inhibitors with favorable predictions by the CoMFA, CoMSIA and GFA models. The reliability of this protocol suggests that it could also be applied to the exploration of lead optimization of other PPI targets.