Comparison of Virtual High-Throughput Screening Methods for the Identification of Phosphodiesterase-5 Inhibitors

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• 作者：Sanna P. Niinivehmas ; Salla I. Virtanen ; Jukka V. Lehtonen ; Pekka A. Postila ; Olli T. Pentika虉inen
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2011
• 出版时间：June 27, 2011
• 年：2011
• 卷：51
• 期：6
• 页码：1353-1363
• 全文大小：930K
• 年卷期：v.51,no.6(June 27, 2011)
• ISSN：1549-960X

文摘

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鈥檚 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.