Identification of druggable concavity in homology model by use of PLB index

Abstract

Identification of the druggable concavity, where druglike molecules are highly inclined to bind, is an important step in structure-based drug design. We previously developed an index named PLB (propensity for ligand binding). The PLB index was proven to be useful in identifying the druggable concavities in the quality X-ray structures of target proteins. Here, we apply the PLB to predicting the druggable concavity in model structures constructed by homology modeling. In this study, we assembled a set of reference proteins that were accurately determined by X-ray analysis in forms of complexes with druglike small molecules. Homology models for the reference proteins were constructed using multiple homologous proteins as templates. The PLB index was then applied to the homology models to predict the druggable concavities. If a template protein in a complex with a druglike small molecule was used, the druggable concavity was predicted well, with a prediction rate of 78%. Interestingly, even when the percent sequence identity between the reference and template proteins was lower than 30, the PLB index could successfully identify the druggable concavity in some cases. This study has demonstrated the practical value of the PLB index in identifying the drugabble concavity in the homology model.