Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.

L-aspartate α-decarboxylase (ADC) belongs to a class of pyruvoyl dependent enzymes and catalyzes the conversion of aspartate to β-alanine in the pantothenate pathway, which is critical for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb). Its presence only in micro-o...

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Autores principales:	Reetu Sharma, Roopa Kothapalli, Antonius M J Van Dongen, 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/bd245b0e21e44ea9962ebf00920f2769
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spelling	oai:doaj.org-article:bd245b0e21e44ea9962ebf00920f27692021-11-18T07:24:05ZChemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.1932-620310.1371/journal.pone.0033521https://doaj.org/article/bd245b0e21e44ea9962ebf00920f27692012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22470451/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203L-aspartate α-decarboxylase (ADC) belongs to a class of pyruvoyl dependent enzymes and catalyzes the conversion of aspartate to β-alanine in the pantothenate pathway, which is critical for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb). Its presence only in micro-organisms, fungi and plants and its absence in animals, particularly human, make it a promising drug target. We have followed a chemoinformatics-based approach to identify potential drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase (MtbADC). The structure-based high throughput virtual screening (HTVS) mode of the Glide program was used to screen 333,761 molecules of the Maybridge, National Cancer Institute (NCI) and Food and Drug Administration (FDA) approved drugs databases. Ligands were rejected if they cross-reacted with S-adenosylmethionine (SAM) decarboxylase, a human pyruvoyl dependent enzyme. The lead molecules were further analyzed for physicochemical and pharmacokinetic parameters, based on Lipinski's rule of five, and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties. This analysis resulted in eight small potential drug-like inhibitors that are in agreement with the binding poses of the crystallographic ADC:fumarate and ADC:isoasparagine complex structures and whose backbone scaffolds seem to be suitable for further experimental studies in therapeutic development against tuberculosis.Reetu SharmaRoopa KothapalliAntonius M J Van DongenKunchithapadam SwaminathanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e33521 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Reetu Sharma Roopa Kothapalli Antonius M J Van Dongen Kunchithapadam Swaminathan Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
description	L-aspartate α-decarboxylase (ADC) belongs to a class of pyruvoyl dependent enzymes and catalyzes the conversion of aspartate to β-alanine in the pantothenate pathway, which is critical for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb). Its presence only in micro-organisms, fungi and plants and its absence in animals, particularly human, make it a promising drug target. We have followed a chemoinformatics-based approach to identify potential drug-like inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase (MtbADC). The structure-based high throughput virtual screening (HTVS) mode of the Glide program was used to screen 333,761 molecules of the Maybridge, National Cancer Institute (NCI) and Food and Drug Administration (FDA) approved drugs databases. Ligands were rejected if they cross-reacted with S-adenosylmethionine (SAM) decarboxylase, a human pyruvoyl dependent enzyme. The lead molecules were further analyzed for physicochemical and pharmacokinetic parameters, based on Lipinski's rule of five, and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties. This analysis resulted in eight small potential drug-like inhibitors that are in agreement with the binding poses of the crystallographic ADC:fumarate and ADC:isoasparagine complex structures and whose backbone scaffolds seem to be suitable for further experimental studies in therapeutic development against tuberculosis.
format	article
author	Reetu Sharma Roopa Kothapalli Antonius M J Van Dongen Kunchithapadam Swaminathan
author_facet	Reetu Sharma Roopa Kothapalli Antonius M J Van Dongen Kunchithapadam Swaminathan
author_sort	Reetu Sharma
title	Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
title_short	Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
title_full	Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
title_fullStr	Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
title_full_unstemmed	Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.
title_sort	chemoinformatic identification of novel inhibitors against mycobacterium tuberculosis l-aspartate α-decarboxylase.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/bd245b0e21e44ea9962ebf00920f2769
work_keys_str_mv	AT reetusharma chemoinformaticidentificationofnovelinhibitorsagainstmycobacteriumtuberculosislaspartateadecarboxylase AT roopakothapalli chemoinformaticidentificationofnovelinhibitorsagainstmycobacteriumtuberculosislaspartateadecarboxylase AT antoniusmjvandongen chemoinformaticidentificationofnovelinhibitorsagainstmycobacteriumtuberculosislaspartateadecarboxylase AT kunchithapadamswaminathan chemoinformaticidentificationofnovelinhibitorsagainstmycobacteriumtuberculosislaspartateadecarboxylase
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Chemoinformatic identification of novel inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase.

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