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.