Investigation of Crystal Structures in Structure-Based Virtual Screening for Protein Kinase Inhibitors

Protein kinases are important drug targets in several therapeutic areas,and structure-based virtual screening (SBVS) is an important strategy in discovering lead compounds for kinase targets. However, there are multiple crystal structures available for each target, and determining which one is the most favorable is a key step in molecular docking for SBVS due to the ligand induce-fit effect. This work aimed to find the most desirable crystal structures for molecular docking by a comprehensive analysis of the protein kinase database which covers 190 different kinases from all eight main kinase families. Through an integrated self-docking and cross-docking evaluation, 86 targets were eventually evaluated on a total of 2608 crystal structures. Results showed that molecular docking has great capability in reproducing conformation of crystallized ligands and for each target, the most favorable crystal structure was selected, and the AGC family outperformed the other family targets based on RMSD comparison. In addition, RMSD values, GlideScore, and corresponding bioactivity data were compared and demonstrated certain relationships. This work provides great convenience for researchers to directly select the optimal crystal structure in SBVS-based kinase drug design and further validates the effectiveness of molecular docking in drug discovery.