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1.
Mini Rev Med Chem ; 16(7): 579-94, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26471968

RESUMO

Structural and electronic factors influencing the inhibition of cyclooxygenase-1 and -2 (COX-1/COX-2) were studied by means of Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking and Density Functional Theory (DFT). A series of structurally diverse compounds containing 209 molecules were classified in accordance with their inhibiting properties, as selectively inhibiting and non-selectively inhibiting COX-2 receptor agents (110 and 99 molecules, correspondingly). The results obtained from the ETM-NN calculations gave us possibility of selecting those pharmacophoric molecular fragments, which allow for the search of new selective inhibitors of COX-2 with high probability of realization. The final selection of pharmacophores and anti-pharmacophores found was taken as a basis for a system designed for the COX-2 inhibitory activity prediction. Analysis of the electron density distribution showed that more effective binding with COX-2 receptor was observed for selective inhibitors. To make an assessment of these interactions, calculations of stabilization energies were carried out for the ligand-receptor complexes. From the results of the docking and from the analysis of electronic structures of active sites of enzymes, some peculiarities of ligand-receptor binding and its influence on the selectivity of the COX-2 relative to COX-1 inhibition were elucidated. 95% of compounds were recognized correctly, as the most active ones, by the system of prediction designed. Thus, the system being the result of the study is capable of predicting the selective inhibitory activity of COX-2 successfully. As a consequence, it can be used both for computer screening and synthesis of potent inhibitors of COX-2 with molecular skeletons that may vary considerably.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Elétrons , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Redes Neurais de Computação , Teoria Quântica , Especificidade por Substrato
2.
J Mol Graph Model ; 60: 79-88, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26117823

RESUMO

Structural and electronic factors influencing selective inhibition of cyclooxygenase-2 and 5-lipoxygenase (COX-2/5-LOX) were studied by using Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking, and Density Functional Theory (DFT) in a large set of molecules. The results of the ETM-NN calculations allowed for the selection of pharmacophoric molecular fragments, which could be taken as a basis for a system capable of predicting the COX-2/5-LOX inhibitory activity. For the more effective extraction of the pharmacophoric molecular fragments, docking of molecules into the active sites of the two enzymes was carried out to get data on the ligand-receptor interaction. To make an assessment of these interactions, stabilization energies were calculated by using Natural Bond Orbital (NBO) analysis. Docking and data on the electronic structures of active sites of enzymes helped to reveal effectively the peculiarities of the ligand-receptor binding. The system for the selective COX-2/5-LOX inhibitory activity prediction that has been developed as the result of the ETM-NN study recognized correctly 93% of compounds as highly active ones. Thus, this system can be successfully used for carrying out computer screening and synthesis of potent inhibitors of COX-2/5-LOX with diverse molecular skeletons.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Redes Neurais de Computação , Algoritmos , Araquidonato 5-Lipoxigenase/química , Domínio Catalítico , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Conjuntos de Dados como Assunto , Humanos , Ligantes , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/metabolismo , Estrutura Molecular , Ligação Proteica , Teoria Quântica , Relação Estrutura-Atividade , Especificidade por Substrato
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