Cargando…

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis...

Descripción completa

Detalles Bibliográficos
Autores principales: Mori, Matteo, Villa, Stefania, Ciceri, Samuele, Colombo, Diego, Ferraboschi, Patrizia, Meneghetti, Fiorella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659263/
https://www.ncbi.nlm.nih.gov/pubmed/34885662
http://dx.doi.org/10.3390/molecules26237082
_version_ 1784612923006517248
author Mori, Matteo
Villa, Stefania
Ciceri, Samuele
Colombo, Diego
Ferraboschi, Patrizia
Meneghetti, Fiorella
author_facet Mori, Matteo
Villa, Stefania
Ciceri, Samuele
Colombo, Diego
Ferraboschi, Patrizia
Meneghetti, Fiorella
author_sort Mori, Matteo
collection PubMed
description The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts.
format Online
Article
Text
id pubmed-8659263
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-86592632021-12-10 An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis Mori, Matteo Villa, Stefania Ciceri, Samuele Colombo, Diego Ferraboschi, Patrizia Meneghetti, Fiorella Molecules Review The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts. MDPI 2021-11-23 /pmc/articles/PMC8659263/ /pubmed/34885662 http://dx.doi.org/10.3390/molecules26237082 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Mori, Matteo
Villa, Stefania
Ciceri, Samuele
Colombo, Diego
Ferraboschi, Patrizia
Meneghetti, Fiorella
An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis
title An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis
title_full An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis
title_fullStr An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis
title_full_unstemmed An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis
title_short An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis
title_sort outline of the latest crystallographic studies on inhibitor-enzyme complexes for the design and development of new therapeutics against tuberculosis
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659263/
https://www.ncbi.nlm.nih.gov/pubmed/34885662
http://dx.doi.org/10.3390/molecules26237082
work_keys_str_mv AT morimatteo anoutlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT villastefania anoutlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT cicerisamuele anoutlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT colombodiego anoutlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT ferraboschipatrizia anoutlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT meneghettifiorella anoutlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT morimatteo outlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT villastefania outlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT cicerisamuele outlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT colombodiego outlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT ferraboschipatrizia outlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis
AT meneghettifiorella outlineofthelatestcrystallographicstudiesoninhibitorenzymecomplexesforthedesignanddevelopmentofnewtherapeuticsagainsttuberculosis