Interaction of wild type, G68R and L125M isoforms of the arylamine-N-acetyltransferase from Mycobacterium tuberculosis with isoniazid: a computational study on a new possible mechanism of resistance

Ramos, Ricardo; Pérez, Juliano Adams; Baptista, Luis Andre; Amorim, Hermes Luís Neubauer de

doi:10.1007/s00894-012-1383-6

Cited by 26 publications

(18 citation statements)

References 55 publications

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“…Although the enoyl-acyl carrier protein reductase InhA is the most described, other mechanisms and enzymes may be involved, such as the human arylamine N-acetyltransferase (NAT) polymorphism, the TB NAT that is also required for mycolic acid synthesis, the MDP1 gene, or even the loss of a sigma factor (34)(35)(36)(37)(38). Mycobacterial NudC may also play an important role in the inactivation of INH (39).…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis-Spoligo-Rifampin-Isoniazid Typing: an All-in-One Assay Technique for Surveillance and Control of Multidrug-Resistant Tuberculosis on Luminex Devices

et al. 2013

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e As a follow-up of the "spoligoriftyping" development, we present here an extension of this technique which includes the detection of isoniazid resistance-associated mutations in a new 59-plex assay, i.e., tuberculosis-spoligo-rifampin-isoniazid typing (TB-SPRINT), running on microbead-based multiplexed systems. This assay improves the synergy between clinical microbiology and epidemiology by providing (i) mutation-based prediction of drug resistance profiles for patient treatment and (ii) genotyping data for tuberculosis (TB) surveillance. This third-generation microbead-based high-throughput assay for TB runs on the Luminex 200 system and on the recently launched MagPix system (Luminex, Austin, TX). Spoligotyping patterns obtained by the TB-SPRINT method were 100% (n ‫؍‬ 85 isolates; 3,655/3,655 spoligotype data points) concordant with those obtained by microbead-based and membrane-based spoligotyping. Genetic drug susceptibility typing provided by the TB-SPRINT method was 100% concordant with resistance locus sequencing (n ‫؍‬ 162 for rpoB gene sequencing and n ‫؍‬ 76 for katG and inhA sequencing). Considering phenotypic drug susceptibility testing (DST) as the reference method, the sensitivity and specificity of TB-SPRINT regarding Mycobacterium tuberculosis complex (n ‫؍‬ 162 isolates) rifampin resistance were both 100%, and those for isoniazid resistance were 90.4% (95% confidence interval, 85 to 95%) and 100%, respectively. Used routinely in national TB reference and specialized laboratories, the TB-SPRINT assay should simultaneously improve personalized medicine and epidemiological surveillance of multidrug-resistant (MDR) TB. This assay is expected to play an emerging role in public health in countries with heavy burdens of MDR TB and/or HIV/TB coinfection. Application of this assay directly to biological samples, as well as development for extensively drug-resistant (XDR) TB detection by inclusion of second-line antituberculosis drug-associated mutations, is under development. With bioinformatical methods and data mining to reduce the number of targets to the most informative ones, locally adapted formats of this technique can easily be developed everywhere.

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Section: Discussionmentioning

confidence: 99%

Tuberculosis-Spoligo-Rifampin-Isoniazid Typing: an All-in-One Assay Technique for Surveillance and Control of Multidrug-Resistant Tuberculosis on Luminex Devices

et al. 2013

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“…Homology modeling was performed following Ramos et al (2012) with MODELER 9v14 (Webb and Sali, 2014) and the amino acid sequences of subunits GluN1a and GluN2B (NCBI GI 645985944 and GI 645985945, respectively). As the crystallographic structure of the PDB NMDA (code 4PE5) are not complete, models were generated by homology modeling (HM-GluN1a and HM-GluN2B) using the crystallographic structure of PDB code 4TLL (GluN1/GluN2B NMDA) as template.…”

Section: Methodsmentioning

confidence: 99%

“…The AutoDock 4.2 package (Morris et al, 2008) was used to prepare proteins (refined models) and ligands for docking calculations using the AutoDock Tools (ADT) module, version 1.5.6, according to Ramos et al (2012). The affinity grid centers were defined on residue Arg120 for COX-2, Tyr513 for NMDA GluN1A and Arg487 for NMDA GluN2B.…”

Section: Methodsmentioning

confidence: 99%

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Antinociceptive Activity of Borreria verticillata: In vivo and In silico Studies

et al. 2017

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Borreria verticillata (L.) G. Mey. known vassourinha has antibacterial, antimalarial, hepatoprotective, antioxidative, analgesic, and anti-inflammatory, however, its antinociceptive action requires further studies. Aim of the study evaluated the antinociceptive activity of B. verticillata hydroalcoholic extract (EHBv) and ethyl acetate fraction (FAc) by in vivo and in silico studies. In vivo assessment included the paw edema test, writhing test, formalin test and tail flick test. Wistar rats and Swiss mice were divided into 6 groups and given the following treatments oral: 0.9% NaCl control group (CTRL), 10 mg/kg memantine (MEM), 10 mg/kg indomethacin (INDO), 500 mg/kg EHBv (EHBv 500), 25 mg/kg FAc (FAc 25) and 50 mg/kg FAc (FAc 50). EHBv, FAc 25 and 50 treatments exhibited anti-edematous and peripheral antinociceptive effects. For in silico assessment, compounds identified in FAc were subjected to molecular docking with COX-2, GluN1a and GluN2B. Ursolic acid (UA) was the compound with best affinity parameters (binding energy and inhibition constant) for COX-2, GluN1a, GluN2B, and was selected for further analysis with molecular dynamics (MD) simulations. In MD simulations, UA exhibited highly frequent interactions with residues Arg120 and Glu524 in the COX-2 active site and NMDA, whereby it might prevent COX-2 and NMDA receptor activation. Treatment with UA 10 mg/Kg showed peripheral and central antinociceptive effect. The antinociceptive effect of B. verticillata might be predominantly attributed to peripheral actions, including the participation of anti-inflammatory components. Ursolic acid is the main active component and seems to be a promising source of COX-2 inhibitors and NMDA receptor antagonists.

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“…Where applicable, detailed interactions were calculated using the LigPlot þ program [30]. A minimum binding of 50% of contacts (sum of hy-drophobic interactions and hydrogen bonds) in the analyzed frames was established as the criterion for binding efficiency [31]. Of the three simulations of each complex (ACE/BPP-BrachyNH2, ACE/des-Pro 8 -BPP-BrachyNH2 and ACE/captopril) were selected for analysis with g_mmpbsa program (section 2.4) simulation with more con-tacts both by hydrogen bonds and hydrophobic interactions.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Structure-function studies of BPP-BrachyNH2 and synthetic analogues thereof with Angiotensin I-Converting Enzyme

Arcanjo

Vasconcelos

Nascimento

et al. 2017

European Journal of Medicinal Chemistry

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The vasoactive proline-rich oligopeptide termed BPP-BrachyNH (H-WPPPKVSP-NH) induces in vitro inhibitory activity of angiotensin I-converting enzyme (ACE) in rat blood serum. In the present study, the removal of N-terminal tryptophan or C-terminal proline from BPP-BrachyNH was investigated in order to predict which structural components are important or required for interaction with ACE. Furthermore, the toxicological profile was assessed by in silico prediction and in vitro MTT assay. Two BPP-BrachyNH analogues (des-Trp-BPP-BrachyNH and des-Pro-BPP-BrachyNH) were synthesized, and in vitro and in silico ACE inhibitory activity and toxicological profile were assessed. The des-Trp-BPP-BrachyNH and des-Pro-BPP-BrachyNH were respectively 3.2- and 29.5-fold less active than the BPP-BrachyNH-induced ACE inhibitory activity. Molecular Dynamic and Molecular Mechanics Poisson-Boltzmann Surface Area simulations (MM-PBSA) demonstrated that the ACE/BBP-BrachyNH complex showed lower binding and van der Wall energies than the ACE/des-Pro-BPP-BrachyNH complex, therefore having better stability. The removal of the N-terminal tryptophan increased the in silico predicted toxicological effects and cytotoxicity when compared with BPP-BrachyNH or des-Pro-BPP-BrachyNH. Otherwise, des-Pro-BPP-BrachyNH was 190-fold less cytotoxic than BPP-BrachyNH. Thus, the removal of C-terminal proline residue was able to markedly decrease both the BPP-BrachyNH-induced ACE inhibitory and cytotoxic effects assessed by in vitro and in silico approaches. In conclusion, the aminoacid sequence of BPP-BrachyNH is essential for its ACE inhibitory activity and associated with an acceptable toxicological profile. The perspective of the interactions of BPP-BrachyNH with ACE found in the present study can be used for development of drugs with differential therapeutic profile than current ACE inhibitors.

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Interaction of wild type, G68R and L125M isoforms of the arylamine-N-acetyltransferase from Mycobacterium tuberculosis with isoniazid: a computational study on a new possible mechanism of resistance

Cited by 26 publications

References 55 publications

Tuberculosis-Spoligo-Rifampin-Isoniazid Typing: an All-in-One Assay Technique for Surveillance and Control of Multidrug-Resistant Tuberculosis on Luminex Devices

Tuberculosis-Spoligo-Rifampin-Isoniazid Typing: an All-in-One Assay Technique for Surveillance and Control of Multidrug-Resistant Tuberculosis on Luminex Devices

Antinociceptive Activity of Borreria verticillata: In vivo and In silico Studies

Structure-function studies of BPP-BrachyNH2 and synthetic analogues thereof with Angiotensin I-Converting Enzyme

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