Molecular Docking Studies and Pharmacophore Modeling of Some Insulin Mimetic Agents from Herbal Sources: A Rational Approach towards Designing of Orally Active Insulin Mimetic Agents

Author(s): Joohee Pradhan*, Sunita Panchawat

Journal Name: Current Traditional Medicine

Volume 6 , Issue 2 , 2020

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Abstract:

Background: Many herbal drugs have been found to possess oral insulin mimetic property as evidenced from the literature. Although, to date there is no efficient, synthetic orally active insulin-mimetic drug available clinically. Computer-Aided Drug Design (CADD) may help in the development of such agents through Pharmacophore modeling.

Objective: The present work is aimed at the In-silico designing of Pharmacophore that defines the structural requirements of a molecule to possess oral insulin-mimetic properties.

Methods: A set of 16 orally active insulin-mimetic natural compounds available through literature was used to develop a structure-based pharmacophore in a “three-step filtration process” comprised of Lipinski’s rule of 5, Minimum binding energy with the receptor and Ghose filter to the Lipinski’s rule for oral bioavailability of the drugs. The selected ligands were docked with phosphorylated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog (PDB ID: 1IR3) using Autodock 4.2 and their interaction with the receptor was analyzed followed by the generation of shared and merged feature pharmacophore by Ligandscout 4.2.1.

Results: There are three important structural features that contribute to interaction with the active site of the insulin receptor: these are hydrogen bond donor groups, hydrogen bond acceptor groups and hydrophobic interactions. It is important to note that positive or negative ionizable groups or the presence of aromatic rings are not important for the activity.

Conclusion: Taking a clue from the developed pharmacophore, one may design new lead having necessary groups required for the insulin-mimetic activity that can be elaborated synthetically to get a series of compounds with possible oral insulin-mimetic activity.

Keywords: Diabetes mellitus, insulin mimetic, orally active, structure-based pharmacophore modeling, docking, hydrophobic interactions.

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Article Details

VOLUME: 6
ISSUE: 2
Year: 2020
Page: [121 - 133]
Pages: 13
DOI: 10.2174/2215083805666191001220342
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