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How are fragments optimized? A retrospective analysis of 145 fragment optimizations.

Abstract：

:Fragment optimizations in nearly 150 fragment-based drug discovery programs reported in the literature during the past fifteen years were investigated. By analyzing physicochemical properties and ligand efficiency indices we found that biochemical detection methods yield hits with superior ligand efficiency and lipophilicity indices than do X-ray and NMR. These advantageous properties are partially preserved in the optimization since higher affinity starting points allow optimizations better balanced between affinity and physicochemical property improvements. Size independent ligand efficiency (SILE) and lipophilic indices (primarily LELP) were found to be appropriate metrics to monitor optimizations. Small and medium enterprises (SME) produce optimized compounds with better properties than do big pharma companies and universities. It appears that the use of target structural information is a major reason behind this finding. Structure-based optimization was also found to dominate successful fragment optimizations that result in clinical candidates. These observations provide optimization guidelines for fragment-based drug discovery programs.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Ferenczy GG,Keserű GM

doi

10.1021/jm301851v

subject

Has Abstract

pub_date

2013-03-28 00:00:00

pages

2478-86

issue

6

eissn

0022-2623

issn

1520-4804

journal_volume

56

pub_type

杂志文章

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