TY - JOUR
T1 - Computational Strategy for Bound State Structure Prediction in Structure-Based Virtual Screening
T2 - A Case Study of Protein Tyrosine Phosphatase Receptor Type O Inhibitors
AU - Hou, Xuben
AU - Rooklin, David
AU - Yang, Duxiao
AU - Liang, Xiao
AU - Li, Kangshuai
AU - Lu, Jianing
AU - Wang, Cheng
AU - Xiao, Peng
AU - Zhang, Yingkai
AU - Sun, Jin Peng
AU - Fang, Hao
N1 - Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/11/26
Y1 - 2018/11/26
N2 - Accurate protein structure in the ligand-bound state is a prerequisite for successful structure-based virtual screening (SBVS). Therefore, applications of SBVS against targets for which only an apo structure is available may be severely limited. To address this constraint, we developed a computational strategy to explore the ligand-bound state of a target protein, by combined use of molecular dynamics simulation, MM/GBSA binding energy calculation, and fragment-centric topographical mapping. Our computational strategy is validated against low-molecular weight protein tyrosine phosphatase (LMW-PTP) and then successfully employed in the SBVS against protein tyrosine phosphatase receptor type O (PTPRO), a potential therapeutic target for various diseases. The most potent hit compound GP03 showed an IC50 value of 2.89 μM for PTPRO and possessed a certain degree of selectivity toward other protein phosphatases. Importantly, we also found that neglecting the ligand energy penalty upon binding partially accounts for the false positive SBVS hits. The preliminary structure-activity relationships of GP03 analogs are also reported.
AB - Accurate protein structure in the ligand-bound state is a prerequisite for successful structure-based virtual screening (SBVS). Therefore, applications of SBVS against targets for which only an apo structure is available may be severely limited. To address this constraint, we developed a computational strategy to explore the ligand-bound state of a target protein, by combined use of molecular dynamics simulation, MM/GBSA binding energy calculation, and fragment-centric topographical mapping. Our computational strategy is validated against low-molecular weight protein tyrosine phosphatase (LMW-PTP) and then successfully employed in the SBVS against protein tyrosine phosphatase receptor type O (PTPRO), a potential therapeutic target for various diseases. The most potent hit compound GP03 showed an IC50 value of 2.89 μM for PTPRO and possessed a certain degree of selectivity toward other protein phosphatases. Importantly, we also found that neglecting the ligand energy penalty upon binding partially accounts for the false positive SBVS hits. The preliminary structure-activity relationships of GP03 analogs are also reported.
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U2 - 10.1021/acs.jcim.8b00548
DO - 10.1021/acs.jcim.8b00548
M3 - Article
C2 - 30299094
AN - SCOPUS:85055475442
SN - 1549-9596
VL - 58
SP - 2331
EP - 2342
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 11
ER -