title: Impact of mobility on structure-based drug design for the MMPs.
abstract: Structure-based approaches for drug design generally do not incorporate solvent effects and dynamic information to predict inhibitor-binding affinity because of practical limitations. The matrix metalloproteinases (MMPs) have previously been demonstrated to exhibit significant mobility in their active sites. This dynamic characteristic significantly complicates the drug design process based on static structures, which was clearly observed for a class of hydroxamic acids containing a butynyl moiety. Compound 1 was expected to be selective against MMP-1 based on predicted steric clashes between the butynyl P1' group and the S1' pocket, but the observation of complex inhibitor dynamics in the NMR structure of MMP-1:1 provides an explanation for the low nanomolar binding to MMP-1.
authors.affiliation: Department of Biological Chemistry Wyeth Research, 87 Cambridge Park Dr., Massachusetts 02140, USA.
authors.forename: Franklin J
authors.initials: FJ
authors.lastname: Moy
authors.forename: Pranab K
authors.initials: PK
authors.lastname: Chanda
authors.forename: James
authors.initials: J
authors.lastname: Chen
authors.forename: Scott
authors.initials: S
authors.lastname: Cosmi
authors.forename: Wade
authors.initials: W
authors.lastname: Edris
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Rush
authors.forename: James
authors.initials: J
authors.lastname: Wilhelm
authors.forename: Robert
authors.initials: R
authors.lastname: Powers
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020781:Matrix Metalloproteinase 1