Comparison of virtual high-throughput screening methods for the identification of phosphodiesterase-5 inhibitors

Niinivehmas, Virtanen, Jukka Lehtonen, Postila, Pentikäinen

Research output: Contribution to journalArticleScientificpeer-review

20 Citations (Scopus)

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.
Original languageUndefined/Unknown
Pages (from-to)1353–1363
JournalJournal of Chemical Information and Modeling
Volume51
Issue number6
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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