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

• Published in: Journal of chemical information and modeling 2014-03, Vol.54 (3), p.987-991
• Main Authors: Kunze, Jens, Todoroff, Nickolay, Schneider, Petra, Rodrigues, Tiago, Geppert, Tim, Reisen, Felix, Schreuder, Herman, Saas, Joachim, Hessler, Gerhard, Baringhaus, Karl-Heinz, Schneider, Gisbert
• Format: Article
• Language: English
• Subjects: Allosteric Regulation - drug effects; Binding Sites; Biochemistry; Drug Design; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV Protease - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1 - enzymology; Human immunodeficiency virus; Humans; Ligands; Molecular Dynamics Simulation; Molecules; Pharmacology; Proteases; Structure-Activity Relationship
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci400712h

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.