TY - JOUR
T1 - Discrete molecular dynamics distinguishes nativelike binding poses from decoys in difficult targets
AU - Proctor, Elizabeth Anne
AU - Yin, Shuangye
AU - Tropsha, Alexander
AU - Dokholyan, Nikolay
N1 - Funding Information:
This work is supported by National Institutes of Health grant R01GM080742 and its ARRA supplement, 3R01GM080742-03S1, to N.V.D., and GM066940 and its ARRA supplement, GM066940-06S1, to A.T. and N.V.D. E.A.P. was partially supported by the Curriculum in Bioinformatics and Computational Biology and National Institutes of Health Predoctoral Fellowship F31AG039266-01 from the National Institute on Aging.
PY - 2012/1/4
Y1 - 2012/1/4
N2 - Virtual screening is one of the major tools used in computer-aided drug discovery. In structure-based virtual screening, the scoring function is critical to identifying the correct docking pose and accurately predicting the binding affinities of compounds. However, the performance of existing scoring functions has been shown to be uneven for different targets, and some important drug targets have proven especially challenging. In these targets, scoring functions cannot accurately identify the native or near-native binding pose of the ligand from among decoy poses, which affects both the accuracy of the binding affinity prediction and the ability of virtual screening to identify true binders in chemical libraries. Here, we present an approach to discriminating native poses from decoys in difficult targets for which several scoring functions failed to correctly identify the native pose. Our approach employs Discrete Molecular Dynamics simulations to incorporate protein-ligand dynamics and the entropic effects of binding. We analyze a collection of poses generated by docking and find that the residence time of the ligand in the native and nativelike binding poses is distinctly longer than that in decoy poses. This finding suggests that molecular simulations offer a unique approach to distinguishing the native (or nativelike) binding pose from decoy poses that cannot be distinguished using scoring functions that evaluate static structures. The success of our method emphasizes the importance of protein-ligand dynamics in the accurate determination of the binding pose, an aspect that is not addressed in typical docking and scoring protocols.
AB - Virtual screening is one of the major tools used in computer-aided drug discovery. In structure-based virtual screening, the scoring function is critical to identifying the correct docking pose and accurately predicting the binding affinities of compounds. However, the performance of existing scoring functions has been shown to be uneven for different targets, and some important drug targets have proven especially challenging. In these targets, scoring functions cannot accurately identify the native or near-native binding pose of the ligand from among decoy poses, which affects both the accuracy of the binding affinity prediction and the ability of virtual screening to identify true binders in chemical libraries. Here, we present an approach to discriminating native poses from decoys in difficult targets for which several scoring functions failed to correctly identify the native pose. Our approach employs Discrete Molecular Dynamics simulations to incorporate protein-ligand dynamics and the entropic effects of binding. We analyze a collection of poses generated by docking and find that the residence time of the ligand in the native and nativelike binding poses is distinctly longer than that in decoy poses. This finding suggests that molecular simulations offer a unique approach to distinguishing the native (or nativelike) binding pose from decoy poses that cannot be distinguished using scoring functions that evaluate static structures. The success of our method emphasizes the importance of protein-ligand dynamics in the accurate determination of the binding pose, an aspect that is not addressed in typical docking and scoring protocols.
UR - http://www.scopus.com/inward/record.url?scp=84855438940&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84855438940&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2011.11.4008
DO - 10.1016/j.bpj.2011.11.4008
M3 - Article
C2 - 22225808
AN - SCOPUS:84855438940
SN - 0006-3495
VL - 102
SP - 144
EP - 151
JO - Biophysical journal
JF - Biophysical journal
IS - 1
ER -