ArticlePloS one2015
Pharmacophore modeling for anti-Chagas drug design using the fragment molecular orbital method.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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16 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- Exploring the interactions of antihistamine with retinoic acid receptor beta (RARB) by molecular dynamics simulations and genome-wide meta-analysis.Journal of molecular graphics & modelling · 2023Pooled it
- Crystallographic snapshots of Trypanosoma cruzi aspartate transcarbamoylase including catalytic intermediates suggest an ordered Bi-Bi reaction mechanism.Scientific reports · 2026Article
- Advances and challenges in the search for new treatments for Chagas disease.Memorias do Instituto Oswaldo Cruz · 2026Review
- Fragment Molecular Orbital Drug Design Consortium (FMODD): Bridging Academia and Industry Through Prospective FMO-Driven Drug Design.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Molecular Dynamics Studies onACS omega · 2025Article
- Evaluation of Pregabalin bioadhesive multilayered microemulsion IOP-lowering eye drops.Journal of controlled release : official journal of the Controlled Release Society · 2024Article
- Discovery of a HiddenACS omega · 2023Article
- Inverse Mixed-Solvent Molecular Dynamics for Visualization of the Residue Interaction Profile of Molecular Probes.International journal of molecular sciences · 2022Article
- Identification of key interactions between SARS-CoV-2 main protease and inhibitor drug candidates.Scientific reports · 2020Article
- Characterizing Interhelical Interactions of G-Protein Coupled Receptors with the Fragment Molecular Orbital Method.Journal of chemical theory and computation · 2020Article
- Integrating Ligand and Target-Driven Based Virtual Screening Approaches WithFrontiers in chemistry · 2020Article
- Molecular Dynamics Simulation reveals the mechanism by which the Influenza Cap-dependent Endonuclease acquires resistance against Baloxavir marboxil.Scientific reports · 2019Article
- Towards good correlation between fragment molecular orbital interaction energies and experimental ICComputational and structural biotechnology journal · 2018Article
- In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease.Scientific reports · 2017Article
- Using the fragment molecular orbital method to investigate agonist-orexin-2 receptor interactions.Biochemical Society transactions · 2016Review
- Identification of potential inhibitors based on compound proposal contest: Tyrosine-protein kinase Yes as a target.Scientific reports · 2015Article
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Authors and funding
15 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundChagas 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
findingsIntermolecular 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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