Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.

In this paper, we investigate the dynamic aspects of the molecular recognition between a small molecule ligand and a flat, exposed protein surface, representing a typical target in the development of protein-protein interaction inhibitors. Specifically, we analyze the complex between the protein Fib...

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Autores principales:	Massimiliano Meli, Katiuscia Pagano, Laura Ragona, Giorgio Colombo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6d46df0df8534984818e40717608e3c5
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spelling	oai:doaj.org-article:6d46df0df8534984818e40717608e3c52021-11-18T08:18:06ZInvestigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.1932-620310.1371/journal.pone.0097153https://doaj.org/article/6d46df0df8534984818e40717608e3c52014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24865844/?tool=EBIhttps://doaj.org/toc/1932-6203In this paper, we investigate the dynamic aspects of the molecular recognition between a small molecule ligand and a flat, exposed protein surface, representing a typical target in the development of protein-protein interaction inhibitors. Specifically, we analyze the complex between the protein Fibroblast Growth Factor 2 (FGF2) and a recently discovered small molecule inhibitor, labeled sm27 for which the binding site and the residues mainly involved in small molecule recognition have been previously characterized. We have approached this problem using microsecond MD simulations and NMR-based characterizations of the dynamics of the apo and holo states of the system. Using direct combination and cross-validation of the results of the two techniques, we select the set of conformational states that best recapitulate the principal dynamic and structural properties of the complex. We then use this information to generate a multi-structure representation of the sm27-FGF2 interaction. We propose this kind of representation and approach as a useful tool in particular for the characterization of systems where the mutual dynamic influence between the interacting partners is expected to play an important role. The results presented can also be used to generate new rules for the rational expansion of the chemical diversity space of FGF2 inhibitors.Massimiliano MeliKatiuscia PaganoLaura RagonaGiorgio ColomboPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 5, p e97153 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Massimiliano Meli Katiuscia Pagano Laura Ragona Giorgio Colombo Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.
description	In this paper, we investigate the dynamic aspects of the molecular recognition between a small molecule ligand and a flat, exposed protein surface, representing a typical target in the development of protein-protein interaction inhibitors. Specifically, we analyze the complex between the protein Fibroblast Growth Factor 2 (FGF2) and a recently discovered small molecule inhibitor, labeled sm27 for which the binding site and the residues mainly involved in small molecule recognition have been previously characterized. We have approached this problem using microsecond MD simulations and NMR-based characterizations of the dynamics of the apo and holo states of the system. Using direct combination and cross-validation of the results of the two techniques, we select the set of conformational states that best recapitulate the principal dynamic and structural properties of the complex. We then use this information to generate a multi-structure representation of the sm27-FGF2 interaction. We propose this kind of representation and approach as a useful tool in particular for the characterization of systems where the mutual dynamic influence between the interacting partners is expected to play an important role. The results presented can also be used to generate new rules for the rational expansion of the chemical diversity space of FGF2 inhibitors.
format	article
author	Massimiliano Meli Katiuscia Pagano Laura Ragona Giorgio Colombo
author_facet	Massimiliano Meli Katiuscia Pagano Laura Ragona Giorgio Colombo
author_sort	Massimiliano Meli
title	Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.
title_short	Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.
title_full	Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.
title_fullStr	Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.
title_full_unstemmed	Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.
title_sort	investigating the dynamic aspects of drug-protein recognition through a combination of md and nmr analyses: implications for the development of protein-protein interaction inhibitors.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/6d46df0df8534984818e40717608e3c5
work_keys_str_mv	AT massimilianomeli investigatingthedynamicaspectsofdrugproteinrecognitionthroughacombinationofmdandnmranalysesimplicationsforthedevelopmentofproteinproteininteractioninhibitors AT katiusciapagano investigatingthedynamicaspectsofdrugproteinrecognitionthroughacombinationofmdandnmranalysesimplicationsforthedevelopmentofproteinproteininteractioninhibitors AT lauraragona investigatingthedynamicaspectsofdrugproteinrecognitionthroughacombinationofmdandnmranalysesimplicationsforthedevelopmentofproteinproteininteractioninhibitors AT giorgiocolombo investigatingthedynamicaspectsofdrugproteinrecognitionthroughacombinationofmdandnmranalysesimplicationsforthedevelopmentofproteinproteininteractioninhibitors
_version_	1718421928060911616

Investigating the dynamic aspects of drug-protein recognition through a combination of MD and NMR analyses: implications for the development of protein-protein interaction inhibitors.

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