Paper Citing NAMD - Abstract
Kunze, Jens; Todoroff, Nickolay; Schneider, Petra; Rodrigues, Tiago; Geppert, Tim; Reisen, Felix; Schreuder, Herman; Saas, Joachim; Hessler, Gerhard; Baringhaus, Karl-Heinz; Schneider, Gisbert
Targeting Dynamic Pockets of HIV-1 Protease by Structure-Based Computational Screening for Allosteric Inhibitors
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 54:987-991, MAR 2014
We present the discovery of low molecular weight inhibitors of human immunodeficiency virus I (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.
