3D QSAR pharmacophore-based virtual screening for the identification of potential inhibitors of tyrosinase.
J Biomol Struct Dyn
; 38(10): 2916-2927, 2020 Jul.
Article
en En
| MEDLINE
| ID: mdl-31334690
ABSTRACT
Tyrosinase plays an important role in melanin biosynthesis and protects skin against ultraviolet radiations. Functional deficiency of tyrosinase results in serious dermatological diseases. Tyrosinase also participates in neuromelanin formation in the human brain, which leads to neurodegeneration resulting in Parkinson's disease. In fruits and vegetables, tyrosinase plays a critical role in senescence, causing undesired browning that results in faster deterioration and shorter shelf lines. The only commercially available tyrosinase is mushroom tyrosinase and it shows the highest homology to the mammalian tyrosinase. Although kojic acid is currently used as a tyrosinase inhibitor, they have serious side effects such as dermatitis, carcinogenesis and hepatotoxicity. Therefore, in order to develop a more active and safer tyrosinase inhibitor, 3D QSAR pharmacophore models were generated based on experimentally known inhibitors. The pharmacophore model, Hypo1, was developed with a large cost difference, high correlation coefficient and low RMS deviation. Hypo1 showed a good spatial arrangement; consisting of five-point features including two hydrogen bond acceptor, one hydrogen bond donor and two hydrophobic features. Hypo1 was further validated by cost analysis, test set and Fisher's randomisation method. Hypo1 was used as a 3D query for screening the in-house drug-like databases, and the hits were further selected by applying ADMET, Lipinski's rule of five and fit value criteria. To identify binding conformations, the obtained hits were subjected to molecular docking. Finally, molecular dynamics simulations revealed the appropriate binding modes of hit compounds. To conclude, we propose the final three hit compounds with new structural scaffolds as a virtual candidate as tyrosinase inhibitors.Communicated by Ramaswamy H. Sarma.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Monofenol Monooxigenasa
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Relación Estructura-Actividad Cuantitativa
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Inhibidores de Proteínas Quinasas
Tipo de estudio:
Clinical_trials
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Diagnostic_studies
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Prognostic_studies
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Screening_studies
Límite:
Humans
Idioma:
En
Revista:
J Biomol Struct Dyn
Año:
2020
Tipo del documento:
Article
País de afiliación:
Pakistán