Pharmacophore modelling, atom-based 3D-QSAR generation and virtual screening of molecules projected for mPGES-1 inhibitory activity.
SAR QSAR Environ Res
; 28(1): 17-39, 2017 Jan.
Article
em En
| MEDLINE
| ID: mdl-28094550
ABSTRACT
COX-2 inhibitors exhibit anticancer effects in various cancer models but due to the adverse side effects associated with these inhibitors, targeting molecules downstream of COX-2 (such as mPGES-1) has been suggested. Even after calls for mPGES-1 inhibitor design, to date there are only a few published inhibitors targeting the enzyme and displaying anticancer activity. In the present study, we have deployed both ligand and structure-based drug design approaches to hunt novel drug-like candidates as mPGES-1 inhibitors. Fifty-four compounds with tested mPGES-1 inhibitory value were used to develop a model with four pharmacophoric features. 3D-QSAR studies were undertaken to check the robustness of the model. Statistical parameters such as r2 = 0.9924, q2 = 0.5761 and F test = 1139.7 indicated significant predictive ability of the proposed model. Our QSAR model exhibits sites where a hydrogen bond donor, hydrophobic group and the aromatic ring can be substituted so as to enhance the efficacy of the inhibitor. Furthermore, we used our validated pharmacophore model as a three-dimensional query to screen the FDA-approved Lopac database. Finally, five compounds were selected as potent mPGES-1 inhibitors on the basis of their docking energy and pharmacokinetic properties such as ADME and Lipinski rule of five.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Relação Quantitativa Estrutura-Atividade
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Inibidores Enzimáticos
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Prostaglandina-E Sintases
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Antineoplásicos
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
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Risk_factors_studies
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Screening_studies
Idioma:
En
Revista:
SAR QSAR Environ Res
Assunto da revista:
SAUDE AMBIENTAL
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Índia