Virtual screening for the discovery of bioactive natural products.

Judith M Rollinger, Hermann Stuppner, Thierry Langer
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Abstract

In this survey the impact of the virtual screening concept is discussed in the field of drug discovery from nature. Confronted by a steadily increasing number of secondary metabolites and a growing number of molecular targets relevant in the therapy of human disorders, the huge amount of information needs to be handled. Virtual screening filtering experiments already showed great promise for dealing with large libraries of potential bioactive molecules. It can be utilized for browsing databases for molecules fitting either an established pharmacophore model or a three dimensional (3D) structure of a macromolecular target. However, for the discovery of natural lead candidates the application of this in silico tool has so far almost been neglected. There are several reasons for that. One concerns the scarce availability of natural product (NP) 3D databases in contrast to synthetic libraries; another reason is the problematic compatibility of NPs with modern robotized high throughput screening (HTS) technologies. Further arguments deal with the incalculable availability of pure natural compounds and their often too complex chemistry. Thus research in this field is time-consuming, highly complex, expensive and ineffective. Nevertheless, naturally derived compounds are among the most favorable source of drug candidates. A more rational and economic search for new lead structures from nature must therefore be a priority in order to overcome these problems. Here we demonstrate some basic principles, requirements and limitations of virtual screening strategies and support their applicability in NP research with already performed studies. A sensible exploitation of the molecular diversity of secondary metabolites however asks for virtual screening concepts that are interfaced with well-established strategies from classical pharmacognosy that are used in an effort to maximize their efficacy in drug discovery. Such integrated virtual screening workflows are outlined here and shall help to motivate NP researchers to dare a step towards this powerful in silico tool.

发现生物活性天然产品的虚拟筛选。
本研究讨论了虚拟筛选概念对从自然界发现药物的影响。面对不断增加的次生代谢物和越来越多与人类疾病治疗相关的分子靶点,需要处理大量的信息。虚拟筛选过滤实验在处理大型潜在生物活性分子库方面已显示出巨大前景。它可用于浏览数据库,寻找符合既定药理模型或大分子靶标三维(3D)结构的分子。然而,迄今为止,在发现天然候选先导药物方面,这种硅学工具的应用几乎被忽视。这有几个原因。其中一个原因是,与合成库相比,天然产物(NP)三维数据库的可用性较低;另一个原因是,NP 与现代机器人高通量筛选(HTS)技术的兼容性存在问题。此外,纯天然化合物的可获得性难以估量,而且其化学性质往往过于复杂。因此,该领域的研究耗时长、高度复杂、成本高昂且效果不佳。然而,天然衍生化合物是最有利的候选药物来源之一。因此,为了克服这些问题,必须优先从自然界中寻找更合理、更经济的新先导结构。在此,我们展示了虚拟筛选策略的一些基本原理、要求和局限性,并通过已完成的研究证明了它们在 NP 研究中的适用性。然而,要合理利用次生代谢物的分子多样性,就必须将虚拟筛选概念与经典药物学中的成熟策略相结合,以最大限度地提高它们在药物发现中的功效。本文概述了这种集成的虚拟筛选工作流程,将有助于激励 NP 研究人员敢于向这种强大的硅学工具迈出一步。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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