On the Value of Homology Models for Virtual Screening: Discovering hCXCR3 Antagonists by Pharmacophore-Based and Structure-Based Approaches
| Autor: | Noeris K. Salam, Jun Xu, Jiming Ye, Hu Ge, Hongzhuan Chen, Arnold T. Hagler, Qiong Gu, Dane Huang |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship Receptors CXCR3 Computer science General Chemical Engineering Drug Evaluation Preclinical Quantitative Structure-Activity Relationship Computational biology Molecular Dynamics Simulation Library and Information Sciences Ligands Inhibitory Concentration 50 Drug Discovery Humans Computer Simulation Homology modeling Virtual screening Binding Sites Drug discovery General Chemistry Combinatorial chemistry Computer Science Applications Docking (molecular) Hit rate Quantum Theory Structure based Pharmacophore |
| Zdroj: | Journal of Chemical Information and Modeling. 52:1356-1366 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/ci300067q |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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