INTEGRATING STRUCTURE AND LIGAND-BASED APPROACHES FOR MODELLING THE HISTONE DEACETYLASE INHIBITION ACTIVITY OF HYDROXAMIC ACID DERIVATIVES


Hai Pham-the, Huong Le-thi-thu

Abstract


 

 Objective: Structure and ligand-based drug design approaches have be been integrated to accurately predict the inhibition activity of hydroxamic acid (HA) derivatives against the histone deacetylase-2 enzyme (HDAC2).

Methods: The “active conformations” of the ligands in the binding site of the enzyme were determined by docking assays. More than 1000 0–3 dimensional molecular descriptors included in Dragon package were calculated and utilized for developing quantitative structure-activity relationship (QSAR) models through a multiple linear regression approach coupled with the genetic algorithm (GA-MLR).

Results: The final model obtained showed suitable robustness and stability, with low correlation between descriptors and good predictive power. QSAR model was then used for screening bioactivity from a series of 36 novel HAs and found five candidates with very good bioactivity (half maximal inhibitory concentration<0.1 μM). Docking experiment revealed the binding mode of these compounds into the active site of HDAC2. Drug-likeness and toxicity profiles of the compounds were checked through chemoinformatics tools.

Conclusion: The results from this study can lead to rational design and synthesis of highly selective and potent HDAC2 inhibitors.


Keywords


Docking, Quantitative structure-activity relationship, Histone deacetylase, Rational drug design, Hydroxamic acid.

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About this article

Title

INTEGRATING STRUCTURE AND LIGAND-BASED APPROACHES FOR MODELLING THE HISTONE DEACETYLASE INHIBITION ACTIVITY OF HYDROXAMIC ACID DERIVATIVES

Topics

Computer aided Drug design

Keywords

Docking, Quantitative structure-activity relationship, Histone deacetylase, Rational drug design, Hydroxamic acid.

DOI

10.22159/ajpcr.2018.v11i2.22995

Date

01-02-2018

Additional Links

Manuscript Submission

Journal

Asian Journal of Pharmaceutical and Clinical Research
Vol 11 Issue 2 February 2018 Page: 198-206

Print ISSN

0974-2441

Online ISSN

2455-3891

Statistics

27 Views | 55 Downloads

Authors & Affiliations

Hai Pham-the
Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13–15 Le Thanh Tong, Hoan Kiem, Hanoi, Vietnam.
Viet Nam

Huong Le-thi-thu
Department of Pharmacy and Pharmacology of Traditional Materials, School of Medicine and Pharmacy, Vietnam National University, Hanoi 144 Xuan Thuy, Cau Giay, Hanoi, Vietnam.
Viet Nam


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