"Virtual fragment linking": an approach to identify potent binders from low affinity fragment hits.

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Crisman TJ, Bender A, Milik M, Jenkins JL, Scheiber J, Sukuru SC, Fejzo J, Hommel U, Davies JW, Glick M

"Virtual fragment linking": an approach to identify potent binders from low affinity fragment hits.

J Med Chem. 2008 Apr 24;51(8):2481-91. doi: 10.1021/jm701314u. Epub 2008 Mar 22.

PubMed ID

18357974 [ View in PubMed

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Abstract

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 (IC 50 < 10microM) 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-(5-HYDROXY-NAPHTHALEN-1-YL)-1,3-BENZOOXAZOL-6-OL	Estrogen receptor beta	IC 50 (nM)	5	N/A	N/A	Details
3-(6-HYDROXY-NAPHTHALEN-2-YL)-BENZO[D]ISOOXAZOL-6-OL	Estrogen receptor beta	IC 50 (nM)	1	N/A	N/A	Details