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Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system: molecular dynamics and quantum calculations

Assis, Letícia C
Author Assis, Letícia C Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil
de Castro, Alexandre A
Author de Castro, Alexandre A Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil
Prandi, Ingrid G
Author Prandi, Ingrid G Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil
Mancini, Daiana T
Author Mancini, Daiana T Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil
de Giacoppo, Juliana O S
Author de Giacoppo, Juliana O S Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil
Savedra, Ranylson M L
Author Savedra, Ranylson M L Laboratory of Molecular Simulation of Material, Department of Physics, Federal University of Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG, CEP 35400-000, Brazil
de Assis, Tamiris M
Author de Assis, Tamiris M Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil
Carregal, Juliano B
Author Carregal, Juliano B Laboratory of Molecular Modeling, Department of Chemistry, Federal University of São João del Rei (UFSJ), Rua Sebastião Gonçalves Coelho 400, Divinópolis, MG, 35501-296, Brazil
da Cunha, Elaine F F
Author da Cunha, Elaine F F Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil
Ramalho, Teodorico Castro
Author Ramalho, Teodorico Castro Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil. teo@dqi.ufla.br Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic. teo@dqi.ufla.br

Journal of molecular modeling. 2018 Oct 02 ; 24 (10) : 303. [epub] 20181002

J Mol Model
ISSN 0948-5023
Source

Language English Country Germany Media electronic

Document type Journal Article

Persistent link https://www.medvik.cz/link/pmid30280322

PubMed 30280322
DOI 10.1007/s00894-018-3837-y
PII: 10.1007/s00894-018-3837-y
Knihovny.cz E-resources

Keywords
AIM, Cantharidin-like inhibitors, Molecular dynamics, QM/MM, Serine/threonine phosphatase 5,
MeSH
Magnesium chemistry MeSH
Enzyme Inhibitors pharmacology MeSH
Nuclear Proteins antagonists & inhibitors chemistry MeSH
Cantharidin analogs & derivatives chemistry pharmacology MeSH
Catalytic Domain MeSH
Cations, Divalent chemistry MeSH
Humans MeSH
Phosphoprotein Phosphatases antagonists & inhibitors chemistry MeSH
Drug Design MeSH
Molecular Dynamics Simulation * MeSH
Check Tag
Humans MeSH
Publication type
Journal Article MeSH
Names of Substances
Magnesium MeSH
Enzyme Inhibitors MeSH
Nuclear Proteins MeSH
Cantharidin MeSH
Cations, Divalent MeSH
protein phosphatase 5 MeSH Browser
Phosphoprotein Phosphatases MeSH

The serine/threonine protein phosphatase type 5 (PP5) is a promising target for designing new antitumor drugs. This enzyme is a member of the PPP phosphatases gene family, which catalyzes a dephosphorylation reaction: a regulatory process in the signal transduction pathway that controls various biological processes. The aim of this work is to study and compare the inhibition of PP5 by ten cantharidin-like inhibitors in order to bring about contributions relevant to the better comprehension of their inhibitory activity. In this theoretical investigation, we used molecular dynamics techniques to understand the role of key interactions that occur in the protein active site; QM calculations were employed to study the interaction mode of these inhibitors in the enzyme. In addition, atoms in molecules (AIM) calculations were carried out to characterize the chemical bonds among the atoms involved and investigate the orbital interactions with their respective energy values. The obtained results suggest that the Arg275, Asn303, His304, His352, Arg400, His427, Glu428, Val429, Tyr451, and Phe446 residues favorably contribute to the interactions between inhibitors and PP5. However, the Asp271 and Asp244 amino acid residues do not favor such interactions for some inhibitors. Through the QM calculations, we can suggest that the reactional energy of the coordination mechanism of these inhibitors in the PP5 active site is quite important and is responsible for the inhibitory activity. The AIM technique employed in this work was essential to get a better comprehension of the transition states acquired from the mechanism simulation. This work offers insights of how cantharidin-like inhibitors interact with human PP5, potentially allowing the design of more specific and even less cytotoxic drugs for cancer treatments. Graphical Abstract Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system.

Center for Basic and Applied Research Faculty of Informatics and Management University of Hradec Kralove Hradec Kralove Czech Republic

Laboratory of Computational Chemistry Department of Chemistry Federal University of Lavras 3027 Campus Universitario Lavras 37200000 Minas Gerais Brazil

Laboratory of Molecular Modeling Department of Chemistry Federal University of São João del Rei Rua Sebastião Gonçalves Coelho 400 Divinópolis MG 35501 296 Brazil

Laboratory of Molecular Simulation of Material Department of Physics Federal University of Ouro Preto Campus Universitário Morro do Cruzeiro Ouro Preto MG CEP 35400 000 Brazil

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