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The Open Form Inducer Approach for Structure-Based Drug Design


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Title: The Open Form Inducer Approach for Structure-Based Drug Design
Authors: Inaoka, Daniel Ken / Iida, Maiko / Tabuchi, Toshiyuki / Honma, Teruki / Lee, Nayoung / Hashimoto, Satoshi / Matsuoka, Shigeru / Kuranaga, Takefumi / Sato, Kazuhito / Shiba, Tomoo / Sakamoto, Kimitoshi / Balogun, Emmanuel Oluwadare / Suzuki, Shigeo / Nara, Takeshi / Rocha, Josmar Rodrigues da / Montanari, Carlos Alberto / Tanaka, Akiko / Inoue, Masayuki / Kita, Kiyoshi / Harada, Shigeharu
Issue Date: 28-Nov-2016
Publisher: Public Library of Science
Citation: PLOS ONE, 11(11), e0167078; 2016
Abstract: Many open form (OF) structures of drug targets were obtained a posteriori by analysis of cocrystals with inhibitors. Therefore, obtaining the OF structure of a drug target a priori will accelerate development of potent inhibitors. In addition to its small active site, Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH) is fully functional in its monomeric form, making drug design approaches targeting the active site and protein-protein interactions unrealistic. Therefore, a novel a priori approach was developed to determination the TcDHODH active site in OF. This approach consists of generating an "OF inducer" (predicted in silico) to bind the target and cause steric repulsion with flexible regions proximal to the active site that force it open. We provide the first proof-of-concept of this approach by predicting and crystallizing TcDHODH in complex with an OF inducer, thereby obtaining the OF a priori with its subsequent use in designing potent and selective inhibitors. Fourteen cocrystal structures of TcDHODH with the designed inhibitors are presented herein. This approach has potential to encourage drug design against diseases where the molecular targets are such difficult proteins possessing small AS volume. This approach can be extended to study open/close conformation of proteins in general, the identification of allosteric pockets and inhibitors for other drug targets where conventional drug design approaches are not applicable, as well as the effective exploitation of the increasing number of protein structures deposited in Protein Data Bank.
URI: http://hdl.handle.net/10069/37359
DOI: 10.1371/journal.pone.0167078
Rights: © 2016 Inaoka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/37359

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