In silico Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity.
Int J Mol Sci
; 21(1)2019 Dec 28.
Article
en En
| MEDLINE
| ID: mdl-31905609
ABSTRACT
Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied in silico. The results of this work will be an asset to paving the way for further design and optimization of novel potent HDAC4 inhibitors for gliomas.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
/
Diseño de Fármacos
/
Inhibidores de Histona Desacetilasas
/
Simulación del Acoplamiento Molecular
/
Histona Desacetilasas
Tipo de estudio:
Guideline
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
CH
/
SUIZA
/
SUÍÇA
/
SWITZERLAND