Targeting Dynamic Pockets of HIV‑1 Protease by Structure-Based Computational Screening for Allosteric Inhibitors

We
present the discovery of low molecular weight inhibitors of
human immunodeficiency virus 1 (HIV-1) protease subtype B that were
identified by structure-based virtual screening as ligands of an allosteric
surface cavity. For pocket identification and prioritization, we performed
a molecular dynamics simulation and observed several flexible, partially
transient surface cavities. For one of these presumable ligand-binding
pockets that are located in the so-called “hinge region”
of the identical protease chains, we computed a receptor-derived pharmacophore
model, with which we retrieved fragment-like inhibitors from a screening
compound pool. The most potent hit inhibited protease activity in
vitro in a noncompetitive mode of action. Although attempts failed
to crystallize this ligand bound to the enzyme, the study provides
proof-of-concept for identifying innovative tool compounds for chemical
biology by addressing flexible protein models with receptor pocket-derived
pharmacophore screening.