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 beta-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.