A1 Refereed original research article in a scientific journal
Comparison of Virtual High-Throughput Screening Methods for the Identification of Phosphodiesterase-5 Inhibitors
Authors: Niinivehmas SP, Virtanen SI, Lehtonen JV, Postila PA, Pentikainen OT
Publisher: AMER CHEMICAL SOC
Publication year: 2011
Journal: Journal of Chemical Information and Modeling
Journal name in source: JOURNAL OF CHEMICAL INFORMATION AND MODELING
Journal acronym: J CHEM INF MODEL
Volume: 51
Issue: 6
First page : 1353
Last page: 1363
Number of pages: 11
ISSN: 1549-9596
DOI: https://doi.org/10.1021/ci1004527
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.
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.
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