Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors.

Autor: Connelly S; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States., Mortenson DE; Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States; Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States., Choi S; Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejon 305-764, Republic of Korea., Wilson IA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States., Powers ET; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States., Kelly JW; Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States; Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States. Electronic address: jkelly@scripps.edu., Johnson SM; Department of Biochemistry & Molecular Biology, Indiana University, School of Medicine, Van Nuys Medical Sciences Building, MS 0013D, 635 Barnhill Dr, Indianapolis, IN 46202, United States. Electronic address: johnstm@iu.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Aug 01; Vol. 27 (15), pp. 3441-3449. Date of Electronic Publication: 2017 May 26.
DOI: 10.1016/j.bmcl.2017.05.080
Abstrakt: Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state-thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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