Molecular modelling and competitive inhibition of a Mycobacterium tuberculosis multidrug-resistance efflux pump

Scaini, João L.; Camargo, Alex; Seus, Vinicius; Groll, Andréa von; Werhli, Adriano Velasque; Silva, Pedro Eduardo Almeida da; Machado, Karina

doi:10.1016/j.jmgm.2018.11.016

Cited by 13 publications

(4 citation statements)

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“…Quantum mechanical methods, such as the density functional theory (DFT) approach, are frequently used in the study of structures, reactions, and molecular properties [42][43][44], but are strictly limited to systems of few hundreds of atoms. In addition, the protein homology modeling has been successfully employed to predict the 3D protein structure, which is essential in many cases when the tertiary or quaternary structure must be studied [45][46][47][48][49].…”

Section: Introductionmentioning

confidence: 99%

The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study

Nogara

Orian

Rocha

2020

Computational Toxicology

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Organoselenium compounds present many pharmacological properties and are promising drugs. However, toxicological effects associated with inhibition of thiol-containing enzymes, such as the δ-aminolevulinic acid dehydratase (δ-AlaD), have been described. The molecular mechanism(s) by which they inhibit thiol-containing enzymes at the atomic level, is still not well known. The use of computational methods to understand the physical-chemical properties and biological activity of chemicals is essential to the rational design of new drugs. In this work, we propose an in silico study to understand the δ-AlaD inhibition mechanism by diphenyl diselenide (DPDS) and its putative metabolite, phenylseleninic acid (PSA), using δ-AlaD enzymes from Homo sapiens (Hsδ-AlaD), Drosophila melanogaster (Dmδ-AlaD) and Cucumis sativus (Csδ-AlaD). Protein modeling homology, molecular docking, and DFT calculations are combined in this study. According to the molecular docking, DPDS and PSA might bind in the Hsδ-AlaD and Dmδ-AlaD active sites interacting with the cysteine residues by Se … S interactions. On the other hand, the DPDS does not access the active site of the Csδ-AlaD (a non-thiol protein), while the PSA interacts with the amino acids residues from the active site, such as the Lys291. These interactions might lead to the formation of a covalent bond, and consequently, to the enzyme inhibition. In fact, DFT calculations (mPW1PW91/def2TZVP) demonstrated that the selenylamide bond formation is energetically favored. The in silico data showed here are in accordance with previous experimental studies, and help us to understand the reactivity and biological activity of organoselenium compounds. dehydratase (mδ-AlaD) or porphobilinogen synthase (PBGS) (EC 4.2.1.24). Since the δ-AlaD is an important enzyme involved in the porphyrins' synthesis, its inhibition can have toxicological consequences [8][9][10][11]. The δ-AlaD catalyzes the asymmetric condensation of two molecules of 5-aminolevulinic acid (δ-aminolevulinic acid -5-Ala), forming the porphobilinogen (PBG), which is the precursor of porphyrins' synthesis (Fig. 1B). In the enzyme active site, each substrate binds at two different subsites (A and P), leading to the regioselective product PBG. The acetic acid and propanoic acid side-chains of PBG originate from the subsites A and P, respectively [12][13][14]. Porphyrins are essential to living beings, particularly to the aerobic life, due to the heme prosthetic group, which is involved in the transport of oxygen (hemoglobin and myoglobin), xenobiotic metabolism (cytochrome P450), protection against peroxides (peroxidases and catalases), and chlorophyll synthesis [13,[15][16][17]. There are two major classes of δ-AlaD: the Zn-dependent enzymes (that are present in mammals, fungi

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Section: Introductionmentioning

confidence: 99%

The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study

Nogara

Orian

Rocha

2020

Computational Toxicology

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“…It can inhibit the formation of glycoprotein by inhibiting the transfer of N-acetylglucosamine-1-phosphate to monophosphate long alcohol. b Scaini et al (2019) . c Prabhu et al (2017) .…”

Section: Resultsmentioning

confidence: 99%

In silico Evolution and Comparative Genomic Analysis of IncX3 Plasmids Isolated From China Over Ten Years

et al. 2021

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IncX3 plasmids are correlated with the dissemination and acquisition of carbapenem resistance in Enterobacteriaceae and have been prevalent in China over the last 10 years. Since the distribution characteristics of IncX3 plasmids across China as well as their evolutionary traits for 10 years remain unclear, here we conducted a retrospective literature review and in silico comparative analysis of IncX3 plasmids in publicly available IncX3 plasmid genomes. IncX3 plasmids distributed in 17 provinces or cities were extracted for analysis, which tend to be specifically associated with hospital-isolated Escherichia coli ST410 from phylogroup A. Although the backbones of IncX3 plasmids have remained highly conservative over the last 10 years, the blaNDM resistance genetic contexts on these plasmids could fall into five subtypes, among which AR_N1_I has been identified in Enterobacter cloacae174 chromosome and AR_N5_I was simultaneously located on IncF and IncA/C plasmids. This suggests that the blaNDM resistance gene environment can spread between different plasmids, between different bacterial genera, or between strains and plasmids, highlighting that it is imperative to adopt more stringent infection control measures targeting IncX3 plasmid spread.

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“…Acquired is due to the modification of binding sites in the cell membrane, through the modification of target proteins. Intrinsic comes from actions such as changes in the efflux pump, caused by environmental exposure to antibiotics, poorly conducted treatment, among others (MAZLUN et al, 2019;SCAINI et al, 2019).…”

Section: Martins Et Al (2013) Carried Out Two Different Extractions O...mentioning

confidence: 99%

Potential of plant extracts against Mycobacterium tuberculosis: an integrative review

Heringer,

Boeira,

Ramos

et al. 2023

PRW

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Mycobacterium tuberculosis (MTB) is the main cause of tuberculosis. For decades, new forms of treatment and new ways of dealing with the growing resistance acquired by this bacterium to first-line drugs have been studied. Medicinal plants are a source of new bioactive compounds with antimicrobial potential. Objective: to investigate which plant species have already been tested and which main secondary metabolites are active against MTB. Methodology: an integrative review that included in vitro experimental studies, carried out around the world, that used medicinal plant extracts to evaluate the antimycobacterial activity by microdilution, with identification of major compounds, against MTB, between 2011 and 2021, the Web of Science and PubMed were used and the descriptors “medicinal plants AND against AND MTB”. Results: 20 species of plants with antimycobacterial activities were found. Four stood out with MIC<10 µg/mL. The variety of secondary metabolites was determinant for antimycobacterial activity, highlighting alkaloids, terpenes and phenolic compounds. Conclusion: the number of secondary metabolites obtained in the extraction is decisive in the antimycobacterial activity.

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Molecular modelling and competitive inhibition of a Mycobacterium tuberculosis multidrug-resistance efflux pump

Cited by 13 publications

References 80 publications

The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study

The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study

In silico Evolution and Comparative Genomic Analysis of IncX3 Plasmids Isolated From China Over Ten Years

Potential of plant extracts against Mycobacterium tuberculosis: an integrative review

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