Table_1_LigBuilder V3: A Multi-Target de novo Drug Design Approach.docx

With the rapid development of systems-based pharmacology and poly-pharmacology, method development for rational design of multi-target drugs has becoming urgent. In this paper, we present the first de novo multi-target drug design program LigBuilder V3, which can be used to design ligands to target multiple receptors, multiple binding sites of one receptor, or various conformations of one receptor. LigBuilder V3 is generally applicable in de novo multi-target drug design and optimization, especially for the design of concise ligands for protein targets with large difference in binding sites. To demonstrate the utility of LigBuilder V3, we have used it to design dual-functional inhibitors targeting HIV protease and HIV reverse transcriptase with three different strategy, including multi-target de novo design, multi-target growing, and multi-target linking. The designed compounds were computational validated by MM/GBSA binding free energy estimation as highly potential multi-target inhibitors for both HIV protease and HIV reverse transcriptase. The LigBuilder V3 program can be downloaded at “http://www.pkumdl.cn/ligbuilder3/”.

随着基于系统的药理学（systems-based pharmacology）与多向药理学（poly-pharmacology）的快速发展，多靶点药物合理设计的方法学开发已迫在眉睫。本文首次报道了从头（de novo）多靶点药物设计程序LigBuilder V3，该程序可用于设计靶向多种受体、单一受体的多个结合位点，或单一受体的多种构象的配体。LigBuilder V3可广泛应用于从头多靶点药物设计与优化，尤其适用于结合位点差异显著的蛋白靶点的简约配体设计。为验证LigBuilder V3的实用性，我们采用三种不同策略——包括多靶点从头设计、多靶点生长以及多靶点连接——设计了靶向HIV蛋白酶（HIV protease）和HIV逆转录酶（HIV reverse transcriptase）的双功能抑制剂。通过MM/GBSA结合自由能估算对设计所得化合物进行计算验证，结果表明其作为针对上述两种靶点的多靶点抑制剂具有极高潜力。可通过网址"http://www.pkumdl.cn/ligbuilder3/"下载LigBuilder V3程序。