RESUMO
The development of sialidase inhibitor-based potential anti-influenza drugs using rational drug design techniques has been of recent interest. The present study details as investigation of the active site of influenza virus sialidase by using the program GRID in an attempt to design more potent inhibitors in the hope they will eventually lead to anti-influenza drugs. A number of different probes (amino, carboxy, hydroxy, methyl, etc) have been used in an effort to determine the functional groups most likely to improve the binding of the starting template 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en). The data have correctly predicted the binding regions for the carboxylate, acetamido (NH and methyl), and glycerol (OH) groups of N-acetylneuraminic acid. Moreover, the data suggest that the addition of certain functionalities (amino group) at the C-4 position should enhance the overall binding.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Neuraminidase/metabolismo , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/enzimologia , Sítios de Ligação , Simulação por Computador , Desenho de Fármacos , Sondas Moleculares , Neuraminidase/química , Conformação ProteicaRESUMO
Two potent inhibitors based on the crystal structure of influenza virus sialidase have been designed. These compounds are effective inhibitors not only of the enzyme, but also of the virus in cell culture and in animal models. The results provide an example of the power of rational, computer-assisted drug design, as well as indicating significant progress in the development of a new therapeutic or prophylactic treatment for influenza infection.
Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Neuraminidase/antagonistas & inibidores , Ácidos Siálicos/farmacologia , Animais , Antivirais/química , Linhagem Celular , Desenho Assistido por Computador , Modelos Animais de Doenças , Feminino , Furões , Guanidinas , Humanos , Vírus da Influenza A/fisiologia , Camundongos , Modelos Moleculares , Piranos , Ovinos , Ácidos Siálicos/química , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacos , ZanamivirRESUMO
An investigation of the crystal structure of cytosolic pig-heart aspartate aminotransferase (AAT, E.C.2.6.1.1) was carried out to determine the structural requirements for ligand recognition by the active site. Structural differences were observed between the two active sites of the AAT dimer. The natural ligand, L-aspartate, was docked into both active sites using various methods. However, due to structural differences, the ligand was able to form all the necessary interactions for initial binding in only one of the active sites. The program GRID (P.J. Goodford, J. Med. Chem. 1985, 28, 849-857) was used to predict favorable binding sites for the functional groups of the aspartate ligand. These binding sites corresponded to the position of the docked aspartate ligand, indicating that substrate recognition takes place before any major conformational changes occur within the enzyme.