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In silico identification of potential dynamin-related protein 1 antagonists: implications for diseases involving mitochondrial dysfunction.

Abstract：

:Mitochondria are the center of metabolism and the critical role of aberrant mitochondrial fission in the onset and progression of a wide range of human diseases such as neurodegenerative disorders, cardiovascular disease, ischemic stroke and diabetes, is slowly becoming recognized. Under physiological conditions, mitochondrial structure is predominantly regulated by cycles of fusion and fission, which is very crucial for the maintenance of cellular homeostasis. Dynamin-related protein 1 is a GTPase that catalyzes the process of mitochondrial fission and is also associated with the excessive fragmentation of mitochondria, impaired mitochondrial dynamics and cell death. Hence, identification of potent and selective antagonists is prerequisite to successfully exploit the therapeutic effects of Drp1 inhibition. In this study, an integrated in silico strategy that includes homology modeling, pharmacophoric, docking analysis and molecular dynamics simulations was employed in designing the potential Drp1 inhibitors. A homology model of Drp1 was generated employing crystal structure of dynamin protein as a template. Pharmacophoric features were developed for the GTPase domain of dynamin-related protein 1 and were used to screen ZINC-database. The obtained hits were docked to the same domain. The binding mode analysis of these ligands showed all the essential binding interactions required in the inhibition of Drp1. Furthermore, explicit solvent simulations were carried out using the two most potential hits to validate the docking analysis and to study the overall stability of the binding site interactions. The present study not only provides a structural model of Drp1 for rational design of apoptotic inhibitors, but also identifies six potential compounds for further development.

journal_name

Comb Chem High Throughput Screen

journal_title

Combinatorial chemistry & high throughput screening

authors

Hanumanthappa P,Rajanikant GK

doi

10.2174/1386207311316010044

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

25-34

issue

eissn

1386-2073

issn

1875-5402

pii

CCHTS-EPUB-53847

journal_volume

pub_type

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In silico identification of potential dynamin-related protein 1 antagonists: implications for diseases involving mitochondrial dysfunction.