TY - JOUR
T1 - Ensemble Docking in Drug Discovery
T2 - How Many Protein Configurations from Molecular Dynamics Simulations are Needed to Reproduce Known Ligand Binding?
AU - Evangelista Falcon, Wilfredo
AU - Ellingson, Sally R.
AU - Smith, Jeremy C.
AU - Baudry, Jerome
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/6/27
Y1 - 2019/6/27
N2 - Ensemble docking in drug discovery or chemical biology uses dynamical simulations of target proteins to generate binding site conformations for docking campaigns. We show that 600 ns molecular dynamics simulations of four G-protein-coupled receptors in their membrane environments generate ensembles of protein configurations that, collectively, are selected by 70 99% of the known ligands of these proteins. Therefore, the process of ligand recognition by conformational selection can be reproduced by combining molecular dynamics and docking calculations. Clustering of the molecular dynamics trajectories, however, does not necessarily identify the protein conformations that are most often selected by the ligands.
AB - Ensemble docking in drug discovery or chemical biology uses dynamical simulations of target proteins to generate binding site conformations for docking campaigns. We show that 600 ns molecular dynamics simulations of four G-protein-coupled receptors in their membrane environments generate ensembles of protein configurations that, collectively, are selected by 70 99% of the known ligands of these proteins. Therefore, the process of ligand recognition by conformational selection can be reproduced by combining molecular dynamics and docking calculations. Clustering of the molecular dynamics trajectories, however, does not necessarily identify the protein conformations that are most often selected by the ligands.
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U2 - 10.1021/acs.jpcb.8b11491
DO - 10.1021/acs.jpcb.8b11491
M3 - Article
C2 - 30695645
AN - SCOPUS:85061995028
SN - 1520-6106
VL - 123
SP - 5189
EP - 5195
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 25
ER -