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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Connelly, Stephen¹  Mortenson, David E.^2,3  Choi, Sungwook⁵  Wilson, Ian A.^1,4  Powers, Evan T.¹  Kelly, Jeffery W.^2,3,4  Johnson, Steven M.⁶ 

[1] Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Dept Chem, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Dept Mol Med, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA

[4] Scripps Res Inst, Skaggs Inst Chem Biol, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA

[5] Chungnam Natl Univ, Dept New Drug Discovery & Dev, 99 Daehak Ro, Daejon 305764, South Korea

[6] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Van Nuys Med Sci Bldg,MS 0013D,635 Barnhill Dr, Indianapolis, IN 46202 USA

关键词: Transthyretin;    TTR;    Amyloid;    Familial amyloid polyneuropathy;    Senile systemic amyloidosis;    Thyroid hormone receptors;    Structural biology;    Structure-based drug design;    In silico docking;    Inhibitor;    Prediction algorithms;   

DOI  :  10.1016/j.bmcl.2017.05.080

来源: Elsevier

【 摘 要 】

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. (C) 2017 Elsevier Ltd. All rights reserved.

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