• MeSH
• antagonisté kyseliny listové chemie   farmakologie   MeSH
• dihydrofolátreduktasa chemie   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• molekulární konformace MeSH
• molekulární modely * MeSH
• molekulární struktura MeSH
• objevování léků MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vodíková vazba MeSH
• Yersinia pestis účinky léků   enzymologie   MeSH
• Publikační typ
• dopisy MeSH

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

Mammalian dihydrofolate reductases (DHFRs) catalyze the reduction of folate more efficiently than the equivalent bacterial enzymes do, despite typically having similar efficiencies for the reduction of their natural substrate, dihydrofolate. In contrast, we show here that DHFR from the hyperthermophilic bacterium Thermotoga maritima can catalyze reduction of folate to tetrahydrofolate with an efficiency similar to that of reduction of dihydrofolate under saturating conditions. Nuclear magnetic resonance and mass spectrometry experiments showed no evidence of the production of free dihydrofolate during either the EcDHFR- or TmDHFR-catalyzed reductions of folate, suggesting that both enzymes perform the two reduction steps without release of the partially reduced substrate. Our results imply that the reaction proceeds more efficiently in TmDHFR than in EcDHFR because the more open active site of TmDHFR facilitates protonation of folate. Because T. maritima lives under extreme conditions where tetrahydrofolate is particularly prone to oxidation, this ability to salvage folate may impart an advantage to the bacterium by minimizing the squandering of a valuable cofactor.

• MeSH
• bakteriální proteiny chemie   genetika   metabolismus   MeSH
• dihydrofolátreduktasa chemie   genetika   metabolismus   MeSH
• druhová specificita MeSH
• Escherichia coli chemie   enzymologie   genetika   MeSH
• exprese genu MeSH
• katalytická doména MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• kyselina listová chemie   metabolismus   MeSH
• NADP chemie   metabolismus   MeSH
• oxidace-redukce MeSH
• protony * MeSH
• sbalování proteinů MeSH
• sekundární struktura proteinů MeSH
• teplota MeSH
• termodynamika MeSH
• tetrahydrofoláty chemie   metabolismus   MeSH
• Thermotoga maritima chemie   enzymologie   genetika   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