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Timmers L.F.S.M.,Instituto Nacional Of Ciencia E Tecnologia Em Tuberculose Inct Tb | Timmers L.F.S.M.,Grande Rio University | Ducati R.G.,Grande Rio University | Sanchez-Quitian Z.A.,Grande Rio University | And 4 more authors.
Journal of Molecular Modeling | Year: 2012

Cytidine Deaminase (CD) is an evolutionarily conserved enzyme that participates in the pyrimidine salvage pathway recycling cytidine and deoxycytidine into uridine and deoxyuridine, respectively. Here, our goal is to apply computational techniques in the pursuit of potential inhibitors of Mycobacterium tuberculosis CD (MtCDA) enzyme activity. Molecular docking simulation was applied to find the possible hit compounds. Molecular dynamics simulations were also carried out to investigate the physically relevant motions involved in the protein-ligand recognition process, aiming at providing estimates for free energy of binding. The proposed approach was capable of identifying a potential inhibitor, which was experimentally confirmed by IC 50 evaluation. Our findings open up the possibility to extend this protocol to different databases in order to find new potential inhibitors for promising targets based on a rational drug design process. © Springer-Verlag 2011. Source

Caceres R.A.,Grande Rio University | Caceres R.A.,Instituto Nacional Of Ciencia E Tecnologia Em Tuberculose Inct Tb | Timmers L.F.S.M.,Grande Rio University | Timmers L.F.S.M.,Instituto Nacional Of Ciencia E Tecnologia Em Tuberculose Inct Tb | And 9 more authors.
Biochimie | Year: 2012

Consumption has been a scourge of mankind since ancient times. This illness has charged a high price to human lives. Many efforts have been made to defeat Mycobacterium tuberculosis (Mt). The M. tuberculosis purine nucleoside phosphorylase (MtPNP) is considered an interesting target to pursuit new potential inhibitors, inasmuch it belongs to the purine salvage pathway and its activity might be involved in the mycobacterial latency process. Here we present the MtPNP crystallographic structure associated with acyclovir and phosphate (MtPNP:ACY:PO 4) at 2.10 resolution. Molecular dynamics simulations were carried out in order to dissect MtPNP:ACY:PO 4 structural features, and the influence of the ligand in the binding pocket stability. Our results revealed that the ligand leads to active site lost of stability, in agreement with experimental results, which demonstrate a considerable inhibitory activity against MtPNP (K i = 150 nM). Furthermore, we observed that some residues which are important in the proper ligand's anchor into the human homologous enzyme do not present the same importance to MtPNP. Therewithal, these findings contribute to the search of new specific inhibitors for MtPNP, since peculiarities between the mycobacterial and human enzyme binding sites have been identified, making a structural-based drug design feasible. © 2011 Elsevier Masson SAS. All rights reserved. Source

Neto B.A.D.,University of Brasilia | Neto B.A.D.,Federal University of Rio Grande do Sul | Lapis A.A.M.,Federal University of Pampa | Lapis A.A.M.,Federal University of Rio Grande do Sul | And 7 more authors.
Molecular BioSystems | Year: 2010

A series of 4,7-π-extended 2,1,3-benzothiadiazoles (BTDs) with different molecular architectures, in particular, the organic dyes based on the 4-(arylethynyl)-7-(4-methoxy)-2,1,3-benzothiazole skeleton, can be used at very low concentrations (down to 10 μM) to detect DNA at 1 ppm in phosphate buffer solutions. Upon binding to DNA, these dyes showed an exponential increase in the fluorescence intensity (hyperchromic effect) and a red shift (1-5 nm) in the long-wavelength emission maxima. Pre-steady state kinetic experiments (stopped-flow) demonstrated the fast dye interaction with the biomacromolecules of DNA with an increase in fluorescence, especially with non-symmetrical BTDs containing an ethynyl spacer. An intercalation model could be proposed based on the photophysical properties, X-ray analysis, and theoretical calculations (ab initio). In this model, the intercalation occurs on the ethynyl side of the BTD, and as a consequence, the PhOMe portion is free to perform the ICT process with the BTD core and stabilizes it in the excited state. © 2010 The Royal Society of Chemistry. Source

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