Kinetic characterization of fragment binding in AmpC β-lactamase by high-throughput molecular simulations.
Small molecules used in fragment-based drug discovery form multiple, promiscuous binding complexes difficult to capture experimentally. Here, we identify such binding poses and their associated energetics and kinetics using molecular dynamics simulations on AmpC β-lactamase. Only one of the crystallographic binding poses was found to be thermodynamically favorable; however, the ligand shows several binding poses within the pocket. This study demonstrates free-binding molecular simulations in the context of fragment-to-lead development and its potential application in drug design.
Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
P
P
Bisignano
S
S
Doerr
M J
MJ
Harvey
A D
AD
Favia
A
A
Cavalli
G
G
De Fabritiis
D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000201:enzymology; D057166:High-Throughput Screening Assays; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000378:metabolism*; D013816:Thermodynamics; D013876:Thiophenes / Q000378:metabolism; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D013876:Thiophenes; C048795:AmpC beta-lactamases; D001618:beta-Lactamases