title: Targeting dynamic pockets of HIV-1 protease by structure-based computational screening for allosteric inhibitors.
abstract: 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.
authors: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) , Vladimir-Prelog-Weg 4 , 8093 Zürich, Switzerland.
authors: Jens
authors: J
authors: Kunze
authors: Nickolay
authors: N
authors: Todoroff
authors: Petra
authors: P
authors: Schneider
authors: Tiago
authors: T
authors: Rodrigues
authors: Tim
authors: T
authors: Geppert
authors: Felix
authors: F
authors: Reisen
authors: Herman
authors: H
authors: Schreuder
authors: Joachim
authors: J
authors: Saas
authors: Gerhard
authors: G
authors: Hessler
authors: Karl-Heinz
authors: KH
authors: Baringhaus
authors: Gisbert
authors: G
authors: Schneider
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001665:Binding Sites; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1