Identification and neuroprotective evaluation of a potential c-Jun N-terminal kinase 3 inhibitor through structure-based virtual screening and in-vitro assay.
J Comput Aided Mol Des
; 34(6): 671-682, 2020 06.
Article
em En
| MEDLINE
| ID: mdl-32040807
ABSTRACT
The c-Jun N-terminal kinase 3 (JNK3) signaling cascade is activated during cerebral ischemia leading to neuronal damage. The present study was carried out to identify and evaluate novel JNK3 inhibitors using in-silico and in-vitro approach. A total of 380 JNK3 inhibitors belonging to different organic groups was collected from the previously reported literature. These molecules were used to generate a pharmacophore model. This model was used to screen a chemical database (SPECS) to identify newer molecules with similar chemical features. The top 1000 hits molecules were then docked against the JNK3 enzyme coordinate following GLIDE rigid receptor docking (RRD) protocol. Best posed molecules of RRD were used during induced-fit docking (IFD), allowing receptor flexibility. Other computational predictions such as binding free energy, electronic configuration and ADME/tox were also calculated. Inferences from the best pharmacophore model suggested that, in order to have specific JNK3 inhibitory activity, the molecules must possess one H-bond donor, two hydrophobic and two ring features. Docking studies suggested that the main interaction between lead molecules and JNK3 enzyme consisted of hydrogen bond interaction with methionine 149 of the hinge region. It was also observed that the molecule with better MM-GBSA dG binding free energy, had greater correlation with JNK3 inhibition. Lead molecule (AJ-292-42151532) with the highest binding free energy (dG = 106.8 Kcal/mol) showed better efficacy than the SP600125 (reference JNK3 inhibitor) during cell-free JNK3 kinase assay (IC50 = 58.17 nM) and cell-based neuroprotective assay (EC50 = 7.5 µM).
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Orgânicos
/
Fármacos Neuroprotetores
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Proteína Quinase 10 Ativada por Mitógeno
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Inibidores de Proteínas Quinases
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
J Comput Aided Mol Des
Assunto da revista:
BIOLOGIA MOLECULAR
/
ENGENHARIA BIOMEDICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Índia