Pharmacophore modeling for anti-Chagas drug design using the fragment molecular orbital method

Ryunosuke Yoshino; Nobuaki Yasuo; Daniel Ken Inaoka; Yohsuke Hagiwara; Kazuki Ohno; Masaya Orita; Masayuki Inoue; Tomoo Shiba; Shigeharu Harada; Teruki Honma; Emmanuel Oluwadare Balogun; Josmar Rodrigues da Rocha; Carlos Alberto Montanari; Kiyoshi Kita; Masakazu Sekijima

doi:10.1371/journal.pone.0125829

Pharmacophore modeling for anti-Chagas drug design using the fragment molecular orbital method

PLoS One. 2015 May 11;10(5):e0125829. doi: 10.1371/journal.pone.0125829. eCollection 2015.

Authors

Affiliations

¹ 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.
² Department of Computer Science, Tokyo Institute of Technology, Meguro, Tokyo, 152-8550, Japan.
³ Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan.
⁴ Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, 305-8585, Japan.
⁵ 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.
⁶ Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan.
⁷ Graduate School of Science and Technology, Kyoto Institute of Technology, Sakyo, Kyoto, 606-8585, Japan.
⁸ Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, 113-0033, Japan; Department of Biochemistry, Ahmadu Bello University, Zaria, 2222, Nigeria.
⁹ Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, 13566-590, Brazil.
¹⁰ 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.

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.

Methodology/principal findings: 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/significance: 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chagas Disease / drug therapy
Chagas Disease / parasitology
Dihydroorotate Dehydrogenase
Drug Design*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Models, Molecular*
Molecular Conformation
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
Oxidoreductases Acting on CH-CH Group Donors / chemistry
Protein Binding
Trypanocidal Agents / chemistry*
Trypanocidal Agents / pharmacology
Trypanosoma cruzi / drug effects
Trypanosoma cruzi / enzymology

Substances

Dihydroorotate Dehydrogenase
Enzyme Inhibitors
Trypanocidal Agents
Oxidoreductases Acting on CH-CH Group Donors

Grants and funding

This research was partially supported by Japanese Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 25870222 and 24240044 (to M.S.). This work was supported in part by Creative Scientific Research Grant 18GS0314 (to K.K.), Grant-in-aid for Scientific Research 18073004 and 26253025 (to K.K.) and 26870119 (to D.K.I.) from the JSPS, and Targeted Proteins Research Program (to K.K. and S.H.) from the Japanese Ministry of Education, Science, Culture, Sports and Technology (MEXT). The authors also acknowledge the support from Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry (to K.K. and S.H.) and JST/JICA, SATREPS (Science and Technology Research Partnership for Sustainable Development) (10000284) to K.K. Astellas Pharma Inc. provided support in the form of salaries for authors YH, KO and MO (YZ1005).