title: The Open Form Inducer Approach for Structure-Based Drug Design.
abstract: Many open form (OF) structures of drug targets were obtained a posteriori by analysis of co-crystals 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 co-crystal 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.
authors.affiliation: School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.|Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Daniel Ken
authors.initials: DK
authors.lastname: Inaoka
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tabuchi
authors.affiliation: Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Lee
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsuoka
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kuranaga
authors.affiliation: Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Shiba
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Agriculture and Life Science, Hirosaki University, Aomori, Japan.
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Emmanuel Oluwadare
authors.initials: EO
authors.lastname: Balogun
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nara
authors.affiliation: Institute of Chemistry of São Carlos, University of São Paulo, São Paulo, Brazil.
authors.forename: Josmar Rodrigues da
authors.initials: JR
authors.lastname: Rocha
authors.affiliation: Institute of Chemistry of São Carlos, University of São Paulo, São Paulo, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Montanari
authors.affiliation: Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.|Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.affiliation: Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Harada
mesh_terms: D020134:Catalytic Domain; D003198:Computer Simulation; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D014344:Trypanocidal Agents / Q000737:chemistry / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D044925:Oxidoreductases Acting on CH-CH Group Donors