Abrogation of AuroraA-TPX2 by novel natural inhibitors: molecular dynamics-based mechanistic analysis.
J Recept Signal Transduct Res
; 35(6): 626-33, 2015.
Article
em En
| MEDLINE
| ID: mdl-26390942
ABSTRACT
INTRODUCTION:
Cancer is characterized by uncontrolled cell growth and genetic instabilities. The human Aurora-A kinase protein plays a crucial role in spindle assembly during mitosis and is activated by another candidate oncogene, targeting protein for Xklp2 (TPX2). It has been proposed that dissociation of Aurora A-TPX2 complex leads to disruption of mitotic spindle apparatus, thereby preventing cell division and further tumor growth. MATERIALS ANDMETHODS:
A large natural compound library was docked against the active site of Aurora A-TPX2 complex. The protein-ligand complexes were subjected to molecular dynamics simulation to ascertain their binding stability. The drug properties of the compounds were analyzed to observe their drug-like properties.RESULTS:
The virtual screening of natural compound library yielded two high scoring compounds, the first compound CTOM [ZINC ID 38143674] (Glide score -9.49) was stable for 17 ns while the second TTOM (Glide score -9.07) was stable for 15 ns. While CTOM interacted with His280, Thr288 of Aurora A and Tyr34, Lys38 of TPX2, TTOM interacted with Arg285 and Arg286 in addition to the residues involved with CTOM.CONCLUSIONS:
We report two natural compounds as potential drugs leads for the disruption of this complex. These ligands show a preferable docking score and have many drugs like properties within in the range of 95% of known drugs. The study provides evidence that CTOM and TTOM can efficiently inhibit the TPX2-mediated activation of Aurora A. Thus, it paves way for an elaborate investigation and establishes the importance of computational approaches as time- and cost-effective techniques.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Produtos Biológicos
/
Proteínas Nucleares
/
Proteínas de Ciclo Celular
/
Bibliotecas de Moléculas Pequenas
/
Simulação de Dinâmica Molecular
/
Aurora Quinase A
/
Proteínas Associadas aos Microtúbulos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article