title: Comparison of virtual high-throughput screening methods for the identification of phosphodiesterase-5 inhibitors.
abstract: Reliable and effective virtual high-throughput screening (vHTS) methods are desperately needed to minimize the expenses involved in drug discovery projects. Here, we present an improvement to the negative image-based (NIB) screening: the shape, the electrostatics, and the solvation state of the target protein's ligand-binding site are included into the vHTS. Additionally, the initial vHTS results are postprocessed with molecular mechanics/generalized Born surface area (MMGBSA) calculations to estimate the favorability of ligand-protein interactions. The results show that docking produces very good early enrichment for phosphodiesterase-5 (PDE-5); however, in general, the NIB and the ligand-based screening performed better with or without the added electrostatics. Furthermore, the postprocessing of the NIB screening results using MMGBSA calculations improved the early enrichment for the PDE-5 considerably, thus, making hit discovery affordable.
authors: Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland.
authors: Sanna P
authors: SP
authors: Niinivehmas
authors: Salla I
authors: SI
authors: Virtanen
authors: Jukka V
authors: JV
authors: Lehtonen
authors: Pekka A
authors: PA
authors: Postila
authors: Olli T
authors: OT
authors: Pentikäinen