Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland.
J Chem Inf Model. 2011 Jun 27;51(6):1353-63. doi: 10.1021/ci1004527. Epub 2011 Jun 1.
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.
可靠且有效的虚拟高通量筛选（vHTS）方法对于降低药物发现项目的成本至关重要。在此，我们对基于负像的（NIB）筛选方法进行了改进：将靶蛋白配体结合位点的形状、静电和溶剂化状态纳入 vHTS 中。此外，还使用分子力学/广义 Born 表面面积（MMGBSA）计算对初始 vHTS 结果进行后处理，以估计配体-蛋白相互作用的有利程度。结果表明，对接对磷酸二酯酶-5（PDE-5）具有很好的早期富集效果；然而，通常情况下，NIB 和基于配体的筛选在加入或不加入静电时表现更好。此外，使用 MMGBSA 计算对 NIB 筛选结果进行后处理可显著提高 PDE-5 的早期富集效果，从而降低发现命中的成本。
