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A Rational Approach to Maximize Success Rate in Target Discovery
Author(s) -
Schneider Martin
Publication year - 2004
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200400913
Subject(s) - drug discovery , computational biology , rational design , drug design , business process discovery , small molecule , drug development , drug , computer science , biology , bioinformatics , pharmacology , genetics , geochemistry , business process modeling , compatibility (geochemistry) , geology , business process
To overcome the problem of high attrition rates in the drug discovery process, an efficient strategy how to identify, select, characterize and validate the most suitable drug targets before embarking on the resource‐intense steps of lead discovery and lead optimization is mandatory. We have implemented such an efficient strategy consisting of (i) Target Selection based on gene expression analyses of drugable target genes in clinical samples and relevant in vitro model systems, to identify candidate targets with a specific tissue distribution and presence in human disease; (ii) Target Assessment exploiting the three‐dimensional structure of proteins for detailed binding site analysis, to estimate the drugability of the protein for small‐molecule inhibitor binding as well as selectivity profiles; and (iii) Target Validation providing evidence for a functional role in in vitro model systems, thus corroborating the biological hypothesis underlying the therapeutic concept. This rational approach has led to the discovery of drug targets for Lead Discovery, maximizing the likelihood for achieving target‐selective inhibition by small‐molecule inhibitors with minimal in vivo side effects and a therapeutic effect based on a sound biological hypothesis.