Manly Charles J, Chandrasekhar Jayaraman, Ochterski Joseph W, Hammer Jack D, Warfield Benjamin B
Neurogen Corporation, 35 N.E. Industrial Road, Branford, CT 06405, United States.
Drug Discov Today. 2008 Feb;13(3-4):99-109. doi: 10.1016/j.drudis.2007.10.019. Epub 2007 Dec 11.
The Hit-to-Lead-to-Candidate process continues to evolve rapidly, and while technological advances offer much potential, the reality often pales to the promise. Conversely, strategies and tactics implementing existing technologies may result in more benefit in the end. This article focuses on some of the thinking and approaches that may improve the efficiency and effectiveness of the beginnings of the drug discovery path. From the perspective of computational chemists, different types of strategy and philosophy of approach will be treated including: considerations of early lead choices, strategies for improving poor leads, multivariate optimization, opportunities for informatics, and engineering good decisions.
从命中到先导再到候选药物的过程仍在迅速发展，虽然技术进步带来了很大潜力，但现实往往与预期相差甚远。相反，实施现有技术的策略和战术最终可能会带来更多益处。本文重点介绍一些可能提高药物发现路径起点效率和有效性的思路和方法。从计算化学家的角度出发，将探讨不同类型的策略和方法理念，包括：早期先导化合物选择的考量、改进不良先导化合物的策略、多变量优化、信息学机会以及做出明智决策。
