Pharmacophore Modeling for Anti-Chagas Drug Design Using the Fragment Molecular Orbital Method

• DOI: 10.1371/journal.pone.0125829
• Publication Date: 2015-05-11T14:18:23Z
• Authors: Ryunosuke Yoshino; Nobuaki Yasuo; Daniel Ken Inaoka; Yohsuke Hagiwara; Kazuki Ohno; Masaya Orita; Masayuki Inoue; Tomoo Shiba; Shigeharu Harada; Teruki Honma; Emmanuel Oluwadar...; Josmar Rodrigues ...; Carlos Alberto Mo...; Kiyoshi Kita; Masakazu Sekijima
• Keywords: Molecular model; Fragment molecular orbital

Background Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that causes severe human health problems. To develop new chemotherapeutic agent for treatment of we predicted pharmacophore model T. cruzi dihydroorotate dehydrogenase (TcDHODH) fragment molecular orbital (FMO) calculation orotate, oxonate, and 43 orotate derivatives. Methodology/Principal Findings Intermolecular interactions in complexes TcDHODH with derivatives were analyzed FMO at MP2/6-31G level. The results indicated moiety, which base these compounds, interacts Lys43, Asn67, Asn194 residues cofactor flavin mononucleotide (FMN), whereas functional groups introduced 5-position strongly interact Lys214 residue. Conclusions/Significance FMO-based interaction energy analyses revealed inhibitor. Hydrogen bond acceptor pharmacophores correspond to Lys43 Lys214, hydrogen donor Asn67 Asn194, aromatic ring corresponds FMN, shows important characteristics compounds inhibit TcDHODH. In addition, residue not conserved between DHODH. Our analysis suggests should preferentially bind TcDHODH, increasing their selectivity. obtained modeling provides insight into structural requirements design inhibitors development as anti-Chagas drugs.