title: Pharmacophore modeling for anti-Chagas drug design using the fragment molecular orbital method.
abstract: BACKGROUND
  Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that causes severe human health problems. To develop a new chemotherapeutic agent for the treatment of Chagas disease, we predicted a pharmacophore model for T. cruzi dihydroorotate dehydrogenase (TcDHODH) by fragment molecular orbital (FMO) calculation for orotate, oxonate, and 43 orotate derivatives.
  
  
  RESULTS
  Intermolecular interactions in the complexes of TcDHODH with orotate, oxonate, and 43 orotate derivatives were analyzed by FMO calculation at the MP2/6-31G level. The results indicated that the orotate moiety, which is the base fragment of these compounds, interacts with the Lys43, Asn67, and Asn194 residues of TcDHODH and the cofactor flavin mononucleotide (FMN), whereas functional groups introduced at the orotate 5-position strongly interact with the Lys214 residue.
  
  
  CONCLUSIONS
  FMO-based interaction energy analyses revealed a pharmacophore model for TcDHODH inhibitor. Hydrogen bond acceptor pharmacophores correspond to Lys43 and Lys214, hydrogen bond donor and acceptor pharmacophores correspond to Asn67 and Asn194, and the aromatic ring pharmacophore corresponds to FMN, which shows important characteristics of compounds that inhibit TcDHODH. In addition, the Lys214 residue is not conserved between TcDHODH and human DHODH. Our analysis suggests that these orotate derivatives should preferentially bind to TcDHODH, increasing their selectivity. Our results obtained by pharmacophore modeling provides insight into the structural requirements for the design of TcDHODH inhibitors and their development as new anti-Chagas drugs.
authors.affiliation: Global Scientific Information and Computing Center, Tokyo Institute of Technology, Meguro, Tokyo, 152-8550, Japan; Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Tokyo, 113-8657, Japan.
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Yoshino
authors.affiliation: Department of Computer Science, Tokyo Institute of Technology, Meguro, Tokyo, 152-8550, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yasuo
authors.affiliation: Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan.
authors.forename: Daniel Ken
authors.initials: DK
authors.lastname: Inaoka
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, 305-8585, Japan.
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Hagiwara
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, 305-8585, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Global Scientific Information and Computing Center, Tokyo Institute of Technology, Meguro, Tokyo, 152-8550, Japan; Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, 305-8585, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Graduate School of Science and Technology, Kyoto Institute of Technology, Sakyo, Kyoto, 606-8585, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Shiba
authors.affiliation: Graduate School of Science and Technology, Kyoto Institute of Technology, Sakyo, Kyoto, 606-8585, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Harada
authors.affiliation: Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
authors.affiliation: Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan; Department of Biochemistry, Ahmadu Bello University, Zaria, 2222, Nigeria.
authors.forename: Emmanuel Oluwadare
authors.initials: EO
authors.lastname: Balogun
authors.affiliation: Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, 13566-590, Brazil.
authors.forename: Josmar Rodrigues
authors.initials: JR
authors.lastname: da Rocha
authors.affiliation: Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, 13566-590, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Montanari
authors.affiliation: Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.affiliation: Global Scientific Information and Computing Center, Tokyo Institute of Technology, Meguro, Tokyo, 152-8550, Japan; Department of Computer Science, Tokyo Institute of Technology, Meguro, Tokyo, 152-8550, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sekijima
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000737:chemistry; D011485:Protein Binding; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; 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