Premium
Rationally Designed Semisynthetic Natural Product Analogues for Stabilization of 14‐3‐3 Protein–Protein Interactions
Author(s) -
Andrei Sebastian A.,
de Vink Pim,
Sijbesma Eline,
Han Ling,
Brunsveld Luc,
Kato Nobuo,
Ottmann Christian,
Higuchi Yusuke
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201806584
Subject(s) - natural product , chemistry , potency , combinatorial chemistry , small molecule , protein–protein interaction , hydrogen bond , protein structure , computational biology , biophysics , stereochemistry , biochemistry , molecule , in vitro , biology , organic chemistry
The natural product family of fusicoccanes are stabilizers of 14‐3‐3 mediated protein–protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X‐ray crystallography confirmed the power of the MD‐based design approach, revealing the potential for an additional hydrogen bond with the 14‐3‐3 protein to lead to significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small‐molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization.