Journal
PLOS ONE
Volume 10, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0125829
Keywords
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Categories
Funding
- Japanese Society for the Promotion of Science (JSPS) KAKENHI Grant [25870222, 24240044]
- Creative Scientific Research Grant [18GS0314]
- JSPS [18073004, 26253025, 26870119]
- Japanese Ministry of Education, Science, Culture, Sports and Technology (MEXT)
- Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry
- JST/JICA, SATREPS (Science and Technology Research Partnership for Sustainable Development) [10000284]
- Astellas Pharma Inc. [YZ1005]
- Grants-in-Aid for Scientific Research [26870119, 15H02776, 26253025, 18073004, 26253003, 25870222, 26440027] Funding Source: KAKEN
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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.
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