title: Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators.
abstract: 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.
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: 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.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: 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.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D020650:Combinatorial Chemistry Techniques / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007527:Isoenzymes / Q000737:chemistry*; D058990:Molecular Targeted Therapy / Q000379:methods; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D054852:Small Molecule Libraries