Inexpensive Method for Selecting Receptor Structures for Virtual Screening.

This article introduces a screening performance index (SPI) to help select from a number of experimental structures one or a few that are more likely to identify more actives among its top hits from virtual screening of a compound library. It achieved this by docking only known actives to the experimental structures without considering a large number of decoys to reduce computational costs. The SPI is calculated by using the docking energies of the actives to all the receptor structures. We evaluated the performance of the SPI by applying it to study eight protein systems: fatty acid binding protein adipocyte FABP4, serine/threonine-protein kinase BRAF, beta-1 adrenergic receptor ADRB1, TGF-beta receptor type I TGFR1, adenosylhomocysteinase SAHH, thyroid hormone receptor beta-1 THB, phospholipase A2 group IIA PA2GA, and cytochrome P450 3a4 CP3A4. We found that the SPI agreed with the results from other popular performance metrics such as Boltzmann-Enhanced Discrimination Receiver Operator Characteristics (BEDROC), Robust Initial Enhancement (RIE), Area Under Accumulation Curve (AUAC), and Enrichment Factor (EF) but is less expensive to calculate. SPI also performed better than the best docking energy, the molecular volume of the bound ligand, and the resolution of crystal structure in selecting good receptor structures for virtual screening. The implications of these findings were further discussed in the context of ensemble docking, in situations when no experimental structure for the targeted protein was available, or under circumstances when quick choices of receptor structures need to be made before quantitative indexes such as the SPI and BEDROC can be calculated.