Target Based Virtual Screening by Docking into Automatically Generated GPCR Models

Abstract

Target based virtual screening (VS) combined with high-throughput measurements is an extremely useful tool to identify small molecule hits for proteins and in particular for G-protein coupled receptors (GPCRs). However, this is a quite difficult process for GPCRs due to the paucity of 3D structural information on these receptors. Therefore, the only possibility for target based VS is to build a structural model of the GPCR to be used for docking. However, GPCR model building is a very time consuming process, if the model should be able to explain all experimental findings and this investment is not always justified, if the model is only used for VS. Thus, a fully automated workflow is presented here, where a large number of GPCR models is built, and the best model is identified to be used for docking. The workflow leads to moderate enrichments with a very low effort. The inputs required are the sequence of the targeted GPCR, a reference ligand with experimental information and a database of small molecules to be used for docking. Manual intervention is recommended at various points, but it is strictly speaking not necessary.