An integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.

Matrix metalloproteinases are a family of Zn-proteases involved in tissue remodeling and in many pathological conditions. Among them MMP-2 is one of the most relevant target in anticancer therapy. Commonly, MMP inhibitors contain a functional group able to bind the zinc ion and responsible for undes...

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Autores principales:	Antonella Di Pizio, Mariangela Agamennone, Massimiliano Aschi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e28085eebf9c4d65874dabe5e048c468
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spelling	oai:doaj.org-article:e28085eebf9c4d65874dabe5e048c4682021-11-18T08:09:27ZAn integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.1932-620310.1371/journal.pone.0047774https://doaj.org/article/e28085eebf9c4d65874dabe5e048c4682012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23144829/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Matrix metalloproteinases are a family of Zn-proteases involved in tissue remodeling and in many pathological conditions. Among them MMP-2 is one of the most relevant target in anticancer therapy. Commonly, MMP inhibitors contain a functional group able to bind the zinc ion and responsible for undesired side effects. The discovery of potent and selective MMP inhibitors not bearing a zinc-binding group is arising for some MMP family members and represents a new opportunity to find selective and non toxic inhibitors.In this work we attempted to get more insight on the inhibition process of MMP-2 by two non-zinc-binding inhibitors, applying a general protocol that combines several computational tools (docking, Molecular Dynamics and Quantum Chemical calculations), that all together contribute to rationalize experimental inhibition data. Molecular Dynamics studies showed both structural and mechanical-dynamical effects produced by the ligands not disclosed by docking analysis. Thermodynamic Integration provided relative binding free energies consistent with experimentally observed activity data. Quantum Chemical calculations of the tautomeric equilibrium involving the most active ligand completed the picture of the binding process. Our study highlights the crucial role of the specificity loop and suggests that enthalpic effect predominates over the entropic one.Antonella Di PizioMariangela AgamennoneMassimiliano AschiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e47774 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Antonella Di Pizio Mariangela Agamennone Massimiliano Aschi An integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.
description	Matrix metalloproteinases are a family of Zn-proteases involved in tissue remodeling and in many pathological conditions. Among them MMP-2 is one of the most relevant target in anticancer therapy. Commonly, MMP inhibitors contain a functional group able to bind the zinc ion and responsible for undesired side effects. The discovery of potent and selective MMP inhibitors not bearing a zinc-binding group is arising for some MMP family members and represents a new opportunity to find selective and non toxic inhibitors.In this work we attempted to get more insight on the inhibition process of MMP-2 by two non-zinc-binding inhibitors, applying a general protocol that combines several computational tools (docking, Molecular Dynamics and Quantum Chemical calculations), that all together contribute to rationalize experimental inhibition data. Molecular Dynamics studies showed both structural and mechanical-dynamical effects produced by the ligands not disclosed by docking analysis. Thermodynamic Integration provided relative binding free energies consistent with experimentally observed activity data. Quantum Chemical calculations of the tautomeric equilibrium involving the most active ligand completed the picture of the binding process. Our study highlights the crucial role of the specificity loop and suggests that enthalpic effect predominates over the entropic one.
format	article
author	Antonella Di Pizio Mariangela Agamennone Massimiliano Aschi
author_facet	Antonella Di Pizio Mariangela Agamennone Massimiliano Aschi
author_sort	Antonella Di Pizio
title	An integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.
title_short	An integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.
title_full	An integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.
title_fullStr	An integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.
title_full_unstemmed	An integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.
title_sort	integrated computational approach to rationalize the activity of non-zinc-binding mmp-2 inhibitors.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/e28085eebf9c4d65874dabe5e048c468
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An integrated computational approach to rationalize the activity of non-zinc-binding MMP-2 inhibitors.

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