Analysis of Neighborhood Behavior in Lead Optimization and Array Design

被引：19

作者：

Papadatos, George ^{[1
,2
]}

Cooper, Anthony W. J. ^{[3
]}

Kadirkamanathan, Visakan ^{[4
]}

Macdonald, Simon J. F. ^{[3
]}

McLay, Iain M. ^{[3
]}

Pickett, Stephen D. ^{[3
]}

Pritchard, John M. ^{[3
]}

Willett, Peter ^{[1
,2
]}

Gillet, Valerie J. ^{[1
,2
]}

机构：

[1] Univ Sheffield, Krebs Inst Biomol Res, Sheffield S1 4DP, S Yorkshire, England

[2] Univ Sheffield, Dept Informat Studies, Sheffield S1 4DP, S Yorkshire, England

[3] GlaxoSmithKline, Med Res Ctr, Stevenage SG1 2NY, Herts, England

[4] Univ Sheffield, Dept Automat Control & Syst Engn, Sheffield S1 3JD, S Yorkshire, England

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2009年 / 49卷 / 02期

基金：

英国工程与自然科学研究理事会;

关键词：

SILICO STRUCTURAL SPACES; VITRO ACTIVITY SPACES; MOLECULAR SIMILARITY; VALIDATION; DESCRIPTORS; DATABASES; RESPECT; INDEX;

D O I：

10.1021/ci800302g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Neighborhood behavior describes the extent to which small structural changes defined by a molecular descriptor are likely to lead to small property changes. This study evaluates two methods for the quantification of neighborhood behavior: the optimal diagonal method of Patterson et al. and the optimality criterion method of Horvath and Jeandenans. The methods are evaluated using twelve different types of fingerprint (both 2D and 3D) with screening data derived from several lead optimization projects at GlaxoSmithKline. The principal focus of the work is the design of chemical arrays during lead optimization, and the study hence considers not only biological activity but also important drug properties such as metabolic stability, permeability, and lipophilicity. Evidence is provided to suggest that the optimality criterion method may provide a better quantitative description of neighborhood behavior than the optimal diagonal method.

引用

页码：195 / 208

页数：14

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