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.
- MeSH
- antagonisté kyseliny listové chemie farmakologie MeSH
- bakteriální proteiny antagonisté a inhibitory MeSH
- Coxiella burnetii účinky léků metabolismus MeSH
- dihydrofolátreduktasa chemie metabolismus MeSH
- katalytická doména MeSH
- lidé MeSH
- ligandy MeSH
- racionální návrh léčiv MeSH
- simulace molekulární dynamiky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In the present work, we propose to design drugs that target the enzyme dihydrofolate redutase (DHFR) as a means of a novel drug therapy against plague. Potential inhibitors of DHFR from Yersinia pestis (YpDHFR) were selected by virtual screening and subjected to docking, molecular dynamics (MD) simulations, and Poisson-Boltzmann surface area method, in order to evaluate their interactions in the active sites of YpDHFR and human DHFR (HssDHFR). The results suggested selectivity for three compounds that were further used to propose the structures of six new potential selective inhibitors for YpDHFR.
- MeSH
- antagonisté kyseliny listové chemie MeSH
- dihydrofolátreduktasa chemie MeSH
- katalytická doména MeSH
- ligandy MeSH
- molekulární konformace MeSH
- racionální návrh léčiv * MeSH
- simulace molekulární dynamiky * MeSH
- simulace molekulového dockingu * MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- Yersinia pestis enzymologie MeSH
- Publikační typ
- časopisecké články MeSH
In order to contribute to a better understanding of the mechanism of action of oximes, we evaluated the affinities of 10 new oximes, derived from pyridine-imidazol bicycled systems, for human acetylcholinesterase (HssAChE) complexed with tabun, by estimating their docking energy values and comparing of the values obtained to known oximes using the software Molegro Virtual Docker (MVD)®. We evaluated the influence of the position of the oxime group as substituent in the structures and, also, the influence of the oxime group syn-anti isomery on the docking score values for all the molecules studied. Results suggest that: the affinities of the 10 new oximes for the tabun inhibited HssAChE active site are better than pralidoxime’s and similar to trimedoxime’s; the meta-pralidoxime could have more affinity for the HssAChE active site and the oximes’ anti isomers could present slightly better affinities for the HssAChE active site than the syn isomers.
- MeSH
- acetylcholinesterasa chemie MeSH
- chemické bojové látky MeSH
- financování organizované MeSH
- molekulární modely MeSH
- neurotoxiny MeSH
- obidoxim chlorid chemická syntéza MeSH
- organofosforové sloučeniny chemie MeSH
- oximy chemie MeSH
- počítačová simulace MeSH
- pralidoximové sloučeniny chemická syntéza MeSH
- racionální návrh léčiv MeSH
- reaktivátory cholinesterázy chemická syntéza MeSH
- trimedoxim chemická syntéza MeSH
- vazebná místa MeSH
