Target Specific Virtual Screening: Optimization of an Estrogen Receptor Screening Platform
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- 作者：Andrew J. S. Knox ; Mary J. Meegan ; Vladimir Sobolev ; Dermot Frost ; Daniela M. Zisterer ; D. Clive Williams ; David G. Lloyd
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：November 1, 2007
- 年：2007
- 卷：50
- 期：22
- 页码：5301 - 5310
- 全文大小：320K
- 年卷期：v.50,no.22(November 1, 2007)
- ISSN：1520-4804
文摘
In this work, we introduce a four-step scoring and filtering procedure, furnishing target specific virtualscreening (TS-VS), which serves to minimize false positives resulting from conformational artifacts of thedocking process and is optimized to converge on novel chemotypes of estrogen receptor alpha (ER). Asa proof of concept, VS of a commercial compound database was undertaken (SPECs database release: Aug2005, 202 054 compounds in total), resulting in the identification of both previously known and novel putativeER scaffolds. Application of distance constraints within TS-VS allowed facile identification of three novelactive ligands with ER binding affinities (IC50) of 1.4 M, 57 nM, and 53 nM. Importantly, they all exhibitedER over ER selectivity, with the most selective being 17-fold. The ligands also displayed low micomolarantiproliferative activity (7-15 M) in the human MCF-7 breast cancer cell line.