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J Med Chem. 2015 Oct 8;58(19):7611-33. doi: 10.1021/acs.jmedchem.5b00229. Epub 2015 Jul 1.

Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators.

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Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, 250012 Jinan, Shandong, P. R. China.
Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
CREST, Japan Science and Technology Agency (JST) , 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.


Currently, the creation of class- and isoform-selective modulators of biologically important targets is a particularly challenging problem because different isoforms within a protein family often show striking similarity in spatial quaternary structure, especially at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agents. In this Perspective, we discuss currently available rational design strategies for obtaining class- and isoform-selective inhibitors and we illustrate these strategies with the aid of specific examples from the recent literature. The strategies covered include: (1) target-derived (-dependent) de novo drug discovery methodologies, and (2) follow-on derivatization approaches from initially identified active molecules (hit-to-lead and lead-to-candidate efforts). We also comment on prospects for further development and integration of strategies to achieve target-specific or isoform-selective inhibition.

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