Protein-ligand interaction study of CpOGA in complex with GlcNAcstatin.
The GlcNAcstatin is a potent inhibitor of O-glycoprotein 2-acetamino-2-deoxy-β-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.
Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110 Belém, PA, Brazil.
Paulo Robson M
PR
Sousa
Nelson Alberto N
NA
de Alencar
Anderson H
AH
Lima
Jerônimo
J
Lameira
Cláudio Nahum
CN
Alves
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D003016:Clostridium perfringens / Q000187:drug effects / Q000201:enzymology; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D007093:Imidazoles; D008024:Ligands; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine