Impact of mobility on structure-based drug design for the MMPs.
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.
Moy
Franklin J
FJ
Department of Biological Chemistry Wyeth Research, 87 Cambridge Park Dr., Massachusetts 02140, USA.
Chanda
Pranab K
PK
Chen
James
J
Cosmi
Scott
S
Edris
Wade
W
Levin
Jeremy I
JI
Rush
Thomas S
TS
Wilhelm
James
J
Powers
Robert
R
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
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020781:Matrix Metalloproteinase 1