title: On the value of homology models for virtual screening: discovering hCXCR3 antagonists by pharmacophore-based and structure-based approaches.
abstract: Human chemokine receptor CXCR3 (hCXCR3) antagonists have potential therapeutic applications as antivirus, antitumor, and anti-inflammatory agents. A novel virtual screening protocol, which combines pharmacophore-based and structure-based approaches, was proposed. A three-dimensional QSAR pharmacophore model and a structure-based docking model were built to virtually screen for hCXCR3 antagonists. The hCXCR3 antagonist binding site was constructed by homology modeling and molecular dynamics (MD) simulation. By combining the structure-based and ligand-based screenings results, 95% of the compounds satisfied either pharmacophore or docking score criteria and would be chosen as hits if the union of the two searches was taken. The false negative rates were 15% for the pharmacophore model, 14% for the homology model, and 5% for the combined model. Therefore, the consistency of the pharmacophore model and the structural binding model is 219/273 = 80%. The hit rate for the virtual screening protocol is 273/286 = 95%. This work demonstrated that the quality of both the pharmacophore model and homology model can be measured by the consistency of the two models, and the false negatives in virtual screening can be reduced by combining two virtual screening approaches.
authors.affiliation: School of Pharmaceutical Sciences & Institute of Human Virology, Sun Yat-sen University, Guangzhou, China 510006.
authors.forename: Dane
authors.initials: D
authors.lastname: Huang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gu
authors.forename: Hu
authors.initials: H
authors.lastname: Ge
authors.forename: Jiming
authors.initials: J
authors.lastname: Ye
authors.forename: Noeris K
authors.initials: NK
authors.lastname: Salam
authors.forename: Arnie
authors.initials: A
authors.lastname: Hagler
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*
chemical_list: C515187:CXCR3 protein, human; D008024:Ligands; D054367:Receptors, CXCR3