PyRod Enables Rational Homology Model-based Virtual Screening Against MCHR1.,Molecular Informatics

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PyRod Enables Rational Homology Model-based Virtual Screening Against MCHR1.
Molecular Informatics ( IF 2.8 ) Pub Date : 2020-04-29 , DOI: 10.1002/minf.202000020
David Schaller ₁ , Gerhard Wolber ₁

Affiliation

Several encouraging pre‐clinical results highlight the melanin‐concentrating hormone receptor 1 (MCHR1) as promising target for anti‐obesity drug development. Currently however, experimentally resolved structures of MCHR1 are not available, which complicates rational drug design campaigns. In this study, we aimed at developing accurate, homologymodel‐based 3D pharmacophores against MCHR1. We show that traditional approaches involving docking of known active small molecules are hindered by the flexibility of binding pocket residues. Instead, we derived three‐dimensional pharmacophores from molecular dynamics simulations by employing our novel open‐source software PyRod. In a retrospective evaluation, the generated 3D pharmacophores were highly predictive returning up to 35 % of active molecules and showing an early enrichment (EF1) of up to 27.6. Furthermore, PyRod pharmacophores demonstrate higher sensitivity than ligand‐based pharmacophores and deliver structural insights, which are key to rational lead optimization.

中文翻译：

PyRod 支持基于 Rational 同源模型的 MCHR1 虚拟筛选。

一些令人鼓舞的临床前结果强调黑色素浓缩激素受体 1 (MCHR1) 是抗肥胖药物开发的有希望的靶点。然而，目前还没有通过实验解析的 MCHR1 结构，这使得合理的药物设计活动变得复杂。在这项研究中，我们的目标是针对 MCHR1 开发准确的、基于同源模型的 3D 药效团。我们表明，涉及已知活性小分子对接的传统方法受到结合口袋残基的灵活性的阻碍。相反，我们使用我们新颖的开源软件 PyRod 从分子动力学模拟中得出了三维药效团。在回顾性评估中，生成的 3D 药效团具有高度预测性，可返回高达 35% 的活性分子，并显示出高达 27.6 的早期富集 (EF1)。此外，PyRod 药效团表现出比基于配体的药效团更高的灵敏度，并提供结构见解，这是合理先导化合物优化的关键。

更新日期：2020-04-29

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