A pharmacophore‐based evolutionary approach for screening selective estrogen receptor modulators

Abstract

We developed a pharmacophorebased evolutionary approach for virtual screening. This tool, termed the Generic Evolutionary Method for molecular DOCKing (GEMDOCK), combines an evolutionary approach with a new pharmacophorebased scoring function. The former integrates discrete and continuous global search strategies with local search strategies to expedite convergence. The latter, integrating an empirical-based energy function and pharmacological preferences (binding-site pharmacological interactions and ligand preferences), simultaneously serves as the scoring function for both molecular docking and postdocking analyses to improve screening accuracy. We apply pharmacological interaction preferences to select the ligands that form pharmacological interactions with target proteins, and use the ligand preferences to eliminate the ligands that violate the electrostatic or hydrophilic constraints. We assessed the accuracy of our approach using human estrogen receptor (ER) and a ligand database from the comparative studies of Bissantz et al. (J Med Chem 2000;43:4759 -4767). Using GEMDOCK, the average goodness-of-hit (GH) score was 0.83 and the average false-positive rate was 0.13% for ER antagonists, and the average GH score was 0.48 and the average false-positive rate was 0.75% for ER agonists. The performance of GEMDOCK was superior to competing methods such as GOLD and DOCK. We found that our pharmacophore-based scoring function indeed was able to reduce the number of false positives; moreover, the resulting pharmacological interactions at the binding site, as well as ligand preferences, were important to the screening accuracy of our experiments. These results suggest that GEMDOCK constitutes a robust tool for virtual database screening. Proteins 2005;59:205-220.

Benchmarking Sets for Molecular Docking

“…Among them, estrogen receptor (ER) 15,20,23,28,29,[37][38][39] and thymidine kinase (TK) 15,19,20,23,28,30,40 have been extensively used to benchmark and evaluate different docking methods and scoring functions. Enrichment studies were also published on several of the other systems, including CDK2 20,41 , P38 MAP kinase 18,20,32,39 , thrombin 20,31,39,41 , factor Xa 38,42 , HIV protease 18,20,40 , DHFR 31,40 , neuraminidase 39 , aldose reductase 31,43 , HIV-RT 20,30 , AChE 31,38 , and COX-2 20,39,44 .…”

Rational Design for Crystallization of β-Lactoglobulin and Vitamin D3 Complex: Revealing a Secondary Binding Site

“…29 The screening accuracies of GEMDOCK were also better than GOLD, FlexX, and DOCK on screening the ligand database for antagonist and agonist ligands of estrogen receptor (ER). 33 GEMDOCK is a better docking tool for assessing the interaction of a specific ligand with each site of LG. We generated 30 docked conformations of each retinol or palmitic acid with whole LG.…”

Computational Identification of Inhibitors of Protein-Protein Interactions

“…The values of A, m, and θ 0 are set to 3.0, 3, and π for sp3-sp3 bond; and to 1.5, 6, and 0 for sp3-sp2 bond. Additional parameters may be used for other types of bonds [100,204].…”