A benchmarking study on virtual ligand screening against homology models of human GPCRs

Citations Over Time

Abstract

Abstract G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures. Among the 19 GPCRs involved in this study, we observed that 10 GPCRs have homology models that have better or comparable performance with respect to the corresponding X-ray structures, making homology models a viable choice for virtual screening. For a small subset of GPCRs, we also explored how certain methods like consensus enrichment and sidechain perturbation affect the utility of homology models in virtual screening, as well as the selectivity between agonists and antagonists. Most notably, consensus enrichment across multiple homology models often yields results comparable to the best performing model, suggesting that ligand candidates predicted with consensus scores from multiple models can be the optimal option in practical applications where the performance of each model cannot be estimated.

Related Papers

• → Status of GPCR Modeling and Docking as Reflected by Community-wide GPCR Dock 2010 Assessment(2011)283 cited
• → Discovery of Novel Chemotypes to a G-Protein-Coupled Receptor through Ligand-Steered Homology Modeling and Structure-Based Virtual Screening(2008)169 cited
• → Discovery of novel α-glucosidase inhibitors based on the virtual screening with the homology-modeled protein structure(2007)123 cited
• → A benchmarking study on virtual ligand screening against homology models of human GPCRs(2018)18 cited
• → A benchmarking study on virtual ligand screening against homology models of human GPCRs(2018)1 cited