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 crystall...

Full description

Saved in:
Bibliographic Details
Published in:Journal of chemical information and modeling 2014-02, Vol.54 (2), p.362-366
Main Authors: Bisignano, P, Doerr, S, Harvey, M. J, Favia, A. D, Cavalli, A, De Fabritiis, G
Format: Article
Language:English
Subjects:
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
beta-Lactamases - chemistry
beta-Lactamases - metabolism
Drug Evaluation, Preclinical
Escherichia coli - enzymology
High-Throughput Screening Assays
Kinetics
Molecular Dynamics Simulation
Protein Binding
Protein Conformation
Small Molecule Libraries - metabolism
Thermodynamics
Thiophenes - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1549-9596
1549-960X
DOI:10.1021/ci4006063