“Virtual Fragment Linking”: An Approach To Identify Potent Binders from Low Affinity Fragment Hits
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- 作者：Thomas J. Crisman ; Andreas Bender ; Mariusz Milik ; Jeremy L. Jenkins ; Josef Scheiber ; Sai Chetan K. Sukuru ; Jasna Fejzo ; Ulrich Hommel ; John W. Davies ; Meir Glick
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：April 24, 2008
- 年：2008
- 卷：51
- 期：8
- 页码：2481 - 2491
- 全文大小：1778K
- 年卷期：v.51,no.8(April 24, 2008)
- ISSN：1520-4804
文摘
In this work we explore the possibilities of using fragment-based screening data to prioritize compounds from a full HTS library, a method we call virtual fragment linking (VFL). The ability of VFL to identify compounds of nanomolar potency based on micromolar fragment binding data was tested on 75 target classes from the WOMBAT database and succeeded in 57 cases. Further, the method was demonstrated for seven drug targets from in-house screening programs that performed both FBS of 8800 fragments and screens of the full library. VFL captured between 28% and 67% of the hits (IC50 < 10µM) in the top 5% of the ranked library for four of the targets (enrichment between 5-fold and 13-fold). Our findings lead us to conclude that proper coverage of chemical space by the fragment library is crucial for the VFL methodology to be successful in prioritizing HTS libraries from fragment-based screening data.