SELECTING PROTEIN STRUCTURE/S FOR DOCKING-BASED VIRTUAL SCREENING: A CASE STUDY ON TYPE II INHIBITORS OF VEGFR-2 KINASE

In this study, 36 crystal structures available with type I-V inhibitors of VEGFR-2 kinase in the RCSB PDB were classified into DFG-in/-out conformation using visual analysis and KLIFS database. The focus was on Type II inhibitors as most kinase inhibitors belong to this category. Therefore, the crystal structures with DFG-out confirmation with a type II inhibitor were selected depending on the resolution and r-free value. 11 selected crystal structures were subjected to self-docking studies and interaction analysis, leading to the elimination of one crystal structure viz. PDB id 3U6J. 10 crystal structures were subjected to cross-docking analysis. No crystal structures were eliminated at this stage as 50% ligands were docked accurately at RMSD cut off ≤ 2Å. These structures were further evaluated for screening performance by calculation of five performance indicating terms. A rank order was established by performance terms. The next stage of selection was the calculation of enrichment factor and assessment of the number of chemical classes retrieved after docking of the DUD set along with actives. Considering the EF values and the rank order of performance terms; 5 crystal structures were eliminated. Lastly, advanced enrichment parameters such as ROC, AUC, RIE, the average number of outranked decoys, and BEDROC were calculated for the remaining 5 structures. After considering all the stages of evaluation, 4ASE was identified as the most suitable crystal structure.