Novartis Institute for BioMedical Research, Global Discovery Chemistry, Computer-Aided Drug Discovery, Forum 1, CH-4002 Basel, Switzerland +41 61 32 45 620 ;
Expert Opin Drug Discov. 2011 Mar;6(3):225-31. doi: 10.1517/17460441.2011.554394.
Identifying novel chemical matter is the focus of many drug discovery efforts. Through these efforts, computer-based de novo design of drug-like molecules, which aim to build an entire molecule 'from scratch', has emerged as a valuable approach to identify novel chemical matter. In this paper, the author discusses the recent research efforts that aim to build, in silico, more chemically accessible molecules, sample more efficiently the chemical space and rank the proposed molecules. The author reviews de novo design algorithms developed between 2008 and 2010 and the issue of validation, and highlights some recent successful applications of de novo design to drug discovery projects. Although research has addressed the lack of synthetic accessibility of the molecules proposed by the first generation of de novo design tools, the lack of accurate scoring function remains a major limitation of structure-based de novo design. However, de novo design is a valuable approach to generate either chemical starting points or ideas.
发现新的化学物质是许多药物发现工作的重点。通过这些努力，基于计算机的从头设计类药物分子的方法已经出现，这种方法旨在“从零开始”构建整个分子，成为发现新化学物质的一种有价值的方法。本文作者讨论了最近旨在构建更具化学可及性分子、更有效地对化学空间进行采样并对提出的分子进行排序的研究工作。作者回顾了 2008 年至 2010 年间开发的从头设计算法和验证问题，并强调了最近将从头设计成功应用于药物发现项目的一些应用。尽管研究已经解决了第一代从头设计工具所提出的分子缺乏合成可及性的问题，但缺乏准确的评分函数仍然是基于结构的从头设计的主要限制。然而，从头设计是生成化学起点或思路的一种有价值的方法。
