Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).

The catalytic activity of L-aspartate α-decarboxylase (ADC) is essential for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb), and has triggered efforts for the development of pharmaceutically active compounds against tuberculosis. The present study is a continuation...

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Autores principales:	Reetu Sharma, Mara Florea, Werner M Nau, Kunchithapadam Swaminathan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a179f203babc4c89b292f030b11b9f82
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spelling	oai:doaj.org-article:a179f203babc4c89b292f030b11b9f822021-11-18T07:04:01ZValidation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).1932-620310.1371/journal.pone.0045947https://doaj.org/article/a179f203babc4c89b292f030b11b9f822012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23029336/?tool=EBIhttps://doaj.org/toc/1932-6203The catalytic activity of L-aspartate α-decarboxylase (ADC) is essential for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb), and has triggered efforts for the development of pharmaceutically active compounds against tuberculosis. The present study is a continuation of our recent chemoinformatics-based design approach for identifying potential drug-like inhibitors against MtbADC. We report an NMR-based protocol that allows label-free and direct monitoring of enzymatic conversion, which we have combined with a systematic testing of reported and newly identified potential inhibitors against MtbADC. Quantification of enzymatic conversion in the absence and presence of inhibitors allowed for a relative measure of the inhibitory effect (k(rel)). Among the newly identified compounds, D-tartrate, L-tartrate, and 2,4-dihydroxypyrimidine-5-carboxylate were found to inhibit the enzyme with k(rel) values of 0.36, 0.38, and 0.54, respectively. In addition to the identification of potential building blocks for the development of therapeutic agents, the current study highlights the importance of electrostatic interactions governing enzyme-inhibitor binding.Reetu SharmaMara FloreaWerner M NauKunchithapadam SwaminathanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 9, p e45947 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Reetu Sharma Mara Florea Werner M Nau Kunchithapadam Swaminathan Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).
description	The catalytic activity of L-aspartate α-decarboxylase (ADC) is essential for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb), and has triggered efforts for the development of pharmaceutically active compounds against tuberculosis. The present study is a continuation of our recent chemoinformatics-based design approach for identifying potential drug-like inhibitors against MtbADC. We report an NMR-based protocol that allows label-free and direct monitoring of enzymatic conversion, which we have combined with a systematic testing of reported and newly identified potential inhibitors against MtbADC. Quantification of enzymatic conversion in the absence and presence of inhibitors allowed for a relative measure of the inhibitory effect (k(rel)). Among the newly identified compounds, D-tartrate, L-tartrate, and 2,4-dihydroxypyrimidine-5-carboxylate were found to inhibit the enzyme with k(rel) values of 0.36, 0.38, and 0.54, respectively. In addition to the identification of potential building blocks for the development of therapeutic agents, the current study highlights the importance of electrostatic interactions governing enzyme-inhibitor binding.
format	article
author	Reetu Sharma Mara Florea Werner M Nau Kunchithapadam Swaminathan
author_facet	Reetu Sharma Mara Florea Werner M Nau Kunchithapadam Swaminathan
author_sort	Reetu Sharma
title	Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).
title_short	Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).
title_full	Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).
title_fullStr	Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).
title_full_unstemmed	Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).
title_sort	validation of drug-like inhibitors against mycobacterium tuberculosis l-aspartate α-decarboxylase using nuclear magnetic resonance (1h nmr).
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/a179f203babc4c89b292f030b11b9f82
work_keys_str_mv	AT reetusharma validationofdruglikeinhibitorsagainstmycobacteriumtuberculosislaspartateadecarboxylaseusingnuclearmagneticresonance1hnmr AT maraflorea validationofdruglikeinhibitorsagainstmycobacteriumtuberculosislaspartateadecarboxylaseusingnuclearmagneticresonance1hnmr AT wernermnau validationofdruglikeinhibitorsagainstmycobacteriumtuberculosislaspartateadecarboxylaseusingnuclearmagneticresonance1hnmr AT kunchithapadamswaminathan validationofdruglikeinhibitorsagainstmycobacteriumtuberculosislaspartateadecarboxylaseusingnuclearmagneticresonance1hnmr
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Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase using nuclear magnetic resonance (1H NMR).

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