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.