Identification of human tau-tubulin kinase 1 inhibitors: an integrated e-pharmacophore-based virtual screening and molecular dynamics simulation.
J Biomol Struct Dyn
; 38(3): 886-900, 2020 02.
Article
em En
| MEDLINE
| ID: mdl-30829560
ABSTRACT
Tau-tubulin kinase 1 inhibitors inhibit tau protein phosphorylation on Ser198, Ser199, Ser202, Ser422, and also in paired helical filaments. We developed receptor-based pharmacophore models by exploiting three TTBK1 protein structures, i.e., 4NFN, 4BTM, and 4BTK. The integrated e-pharmacophore based virtual screening and molecular dynamics simulation recognized four hits viz. ZINC14644839, ZINC00012956, ZINC91332506, and ZINC69775110 as TTBK1 inhibitors. The Glide XP docking energies (-8.48 to -10.71 kcal.mol-1) of hits were better than cocrystal ligand of 4NFN protein structure (-8.37 kcal.mol-1). Among the hits, ZINC14644839 possessed best binding energy with four hydrogen bonding interactions. The inhibitors showed acceptable calculated ADME and blood-brain barrier permeability properties and could be potential TTBK1 inhibitors for neurodegenerative diseases.Communicated by Ramaswamy H. Sarma.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
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Inibidores de Proteínas Quinases
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Avaliação Pré-Clínica de Medicamentos
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Simulação de Dinâmica Molecular
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
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Screening_studies
Idioma:
En
Revista:
J Biomol Struct Dyn
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Índia