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1.
Comput Biol Med ; 43(10): 1334-40, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24034724

RESUMO

Calpain-10 (CAPN10) is a cysteine protease that is activated by intracellular calcium (Ca(2+)) and known to be involved in diseases such as cancer, heart attack, and stroke. A role for the CAPN10 gene in diabetes mellitus type II was recently identified. Hyper activation of the enzyme initiates a series of destructive cycles that can cause irreversible damage to cells. The development of inhibitors may be useful as therapeutic agents for a number of calpainopathies. In this paper, we have used the homology modelling technique to determine the 3D structure of calpain-10 from Homo sapiens. The model of calpain-10 obtained by homology modelling suggests that its active site is conserved among family members and the main interactions are similar to those observed for µ-calpain. Structural analysis revealed that there are small differences in the charge distribution and molecular surface of the enzyme. These differences are probably less dependent on calcium for calpain-10 than they are for µ-calpain. In addition, the ion pair Cys(-)/His(+) formation was observed using of Molecular Dynamics (MD) simulations that were based upon hybrid quantum mechanical/molecular mechanical (QM/MM) approaches. Finally, the binding of the SNJ-1715 inhibitor to calpain-10 was investigated in order to further understand the mechanism of inhibition of calpain-10 by this inhibitor at the molecular level.


Assuntos
Calpaína/química , Tioureia/análogos & derivados , Sequência de Aminoácidos , Calpaína/antagonistas & inibidores , Calpaína/metabolismo , Humanos , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Reprodutibilidade dos Testes , Alinhamento de Sequência , Eletricidade Estática , Tioureia/química , Tioureia/metabolismo , Tioureia/farmacologia
2.
Chem Biol Drug Des ; 81(2): 284-90, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23066949

RESUMO

The GlcNAcstatin is a potent inhibitor of O-glycoprotein 2-acetamino-2-deoxy-ß-D-glucopyranosidase, which has been related with type II diabetes and neurodegenerative disorders. Herein, hybrid quantum mechanics/molecular mechanics, molecular dynamics simulations, and potential of mean force were employed to study the interactions established between GlcNAcstatin and a bacterial O-GlcNAcase enzyme from Clostridium perfringens. The results reveal that the imidazole nitrogen atom of GlcNAcstatin has shown a better interaction with the active site of Clostridium perfringens in its protonated form, which is compatible with a substrate-assisted reaction mechanism involving two conserved aspartate residues (297 and 298). Furthermore, the quantum mechanics/molecular mechanics-molecular dynamics simulations appointed a strong interaction between Asp401, Asp298, and Asp297 residues and the GlcNAcstatin inhibitor, which is in accordance with experimental data. Lastly, these results may contribute to understand the molecular mechanism of inhibition of Clostridium perfringens by GlcNAcstatin inhibitor and, consequently, this study might be useful to design new molecules with more interesting inhibitory activity.


Assuntos
Acetilglucosamina/análogos & derivados , Acetilglucosamina/química , Imidazóis/química , beta-N-Acetil-Hexosaminidases/química , Acetilglucosamina/farmacologia , Domínio Catalítico , Clostridium perfringens/efeitos dos fármacos , Clostridium perfringens/enzimologia , Imidazóis/farmacologia , Ligantes , Modelos Moleculares , Simulação de Dinâmica Molecular , Termodinâmica , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , beta-N-Acetil-Hexosaminidases/metabolismo
3.
J Chem Inf Model ; 52(10): 2775-83, 2012 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-22937904

RESUMO

The substitution of serine and threonine residues in nucleocytoplasmic proteins with 2-acetamido-2-deoxy-ß-D-glucopyranose (O-GlcNAc) residues is an essential post-translational modification found in many multicellular eukaryotes. O-glycoprotein 2-acetamino-2-deoxy-ß-D-glucopyranosidase (O-GlcNAcase) hydrolyzes O-GlcNAc residues from post-translationally modified serine/threonine residues of nucleocytoplasmic protein. O-GlcNAc has been implicated in several disease states such as cancer, Alzheimer's disease, and type II diabetes. For this paper, a model of the human O-GlcNAcase (hOGA) enzyme based on the X-ray structures of bacterial Clostridium perfringens (CpNagJ) and Bacteroides thetaiotaomicrometer (BtOGA) homologues has been generated through molecular homology modeling. In addition, molecular docking, molecular dynamics (MD) simulations, and Linear Interaction Energy (LIE) were employed to determine the bind for derivatives of two potent inhibitors: O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2'-methyl-R-D-glucopyranoso-[2,1-d]-Δ2'-thiazoline (NAG-thiazoline), with hOGA. The results show that the binding free energy calculations using the Linear Interaction Energy (LIE) are correlated with inhibition constant values. Therefore, the model of the human O-GlcNAcase (hOGA) obtained here may be used as a target for rational design of new inhibitors.


Assuntos
Acetilglucosamina/análogos & derivados , Proteínas de Bactérias/química , Simulação de Acoplamento Molecular , Oximas/química , Fenilcarbamatos/química , Tiazóis/química , beta-N-Acetil-Hexosaminidases/química , Acetilglucosamina/química , Proteínas de Bactérias/antagonistas & inibidores , Bacteroides/química , Bacteroides/enzimologia , Sítios de Ligação , Clostridium perfringens/química , Clostridium perfringens/enzimologia , Cristalografia por Raios X , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Cinética , Ligantes , Ligação Proteica , Conformação Proteica , Homologia Estrutural de Proteína , Termodinâmica , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores
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