title: A technique to study molecular recognition in drug design: preliminary application of free energy derivatives to inhibition of a malarial cysteine protease.
abstract: We present molecular dynamics studies on model complexes of inhibitors of a malarial cysteine protease. The initial model for such complexes came from the model building of the protein using its homology with other cysteine proteases and calculations using DOCK to generate new lead compounds. Some of the initial model-built structures were quite stable for 100 psec of dynamics; others moved significantly from their model-built orientation. We also calculated the free energy derivatives at each atom in the inhibitor, both in water and in the binding site. The results of these calculations suggest directions for the design of new, more potent enzyme inhibitors and agree qualitatively with some of the experimental findings. Nonetheless, we stress that we have only used this methodology in an interpretive rather than a predictive manner.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143, USA.
authors.forename: P
authors.initials: P
authors.lastname: Cieplak
authors.forename: P A
authors.initials: PA
authors.lastname: Kollman
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D008288:Malaria / Q000201:enzymology*; D008956:Models, Chemical; D008958:Models, Molecular
chemical_list: D015853:Cysteine Proteinase Inhibitors; D003546:Cysteine Endopeptidases