title: Analysis of Coxiela burnetti dihydrofolate reductase via in silico docking with inhibitors and molecular dynamics simulation.
abstract: Coxiella burnetii is a gram-negative bacterium able to infect several eukaryotic cells, mainly monocytes and macrophages. It is found widely in nature with ticks, birds, and mammals as major hosts. C. burnetii is also the biological warfare agent that causes Q fever, a disease that has no vaccine or proven chemotherapy available. Considering the current geopolitical context, this fact reinforces the need for discovering new treatments and molecular targets for drug design against C. burnetii. Among the main molecular targets against bacterial diseases reported, the enzyme dihydrofolate reductase (DHFR) has been investigated for several infectious diseases. In the present work, we applied molecular modeling techniques to evaluate the interactions of known DHFR inhibitors in the active sites of human and C. burnetii DHFR (HssDHFR and CbDHFR) in order to investigate their potential as selective inhibitors of CbDHFR. Results showed that most of the ligands studied compete for the binding site of the substrate more effectively than the reference drug trimethoprim. Also the most promising compounds were proposed as leads for the drug design of potential CbDHFR inhibitors.
authors.affiliation: a Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMCBD) , Military Institute of Engineering , Rio de Janeiro , RJ , Brazil.
authors.forename: Felipe Rodrigues
authors.initials: FR
authors.lastname: de Souza
authors.affiliation: b Department of Chemistry , Federal University of Viçosa , Viçosa , MG , Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Guimarães
authors.affiliation: c Faculty of Technology , University of the State of Rio de Janeiro , Resende , RJ , Brazil.
authors.forename: Teobaldo
authors.initials: T
authors.lastname: Cuya
authors.affiliation: d Department of Chemistry , Federal University of Lavras , Lavras , MG , Brazil.
authors.forename: Matheus Puggina
authors.initials: MP
authors.lastname: de Freitas
authors.affiliation: e Federal Institute of Education , Science and Technology , Vila Velha , ES , Brazil.
authors.forename: Arlan da Silva
authors.initials: ADS
authors.lastname: Gonçalves
authors.affiliation: f Department of Chemistry and Biochemistry , Concordia University , Montreal , Canada.
authors.forename: Pat
authors.initials: P
authors.lastname: Forgione
authors.affiliation: a Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMCBD) , Military Institute of Engineering , Rio de Janeiro , RJ , Brazil.|f Department of Chemistry and Biochemistry , Concordia University , Montreal , Canada.|g Faculty of Management and Informatics , University Hradec Kralove , Hradec Kralove , Czech Republic.
authors.forename: Tanos Celmar
authors.initials: TC
authors.lastname: Costa França
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D016997:Coxiella burnetii / Q000187:drug effects* / Q000378:metabolism*; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D005493:Folic Acid Antagonists; D008024:Ligands; D013762:Tetrahydrofolate Dehydrogenase
keywords: Coxiella burnetii; Q fever; dihydrofolate reductase; docking; molecular dynamics