Abstract
Background: Leptin is secreted by adipocytes, transported into the brain and binds to its receptor in the hypothalamus, and activates JAK-STAT3, leading to increase in “anorexigenic peptides” which normally inhibit food consumption and reduce weight.Objectives: In the current study, a hybrid approach of molecular docking and virtual screening was performed, for the identification of active alternative compounds to manage obesity disorders.Methods: Screening was performed using structure-based drug design against approved FDA drugs; molecular modeling was done using AutoDockVina; only top 10 conformers’ ligands with highest and best scores were selected. In order to increase the likelihood of successful docking, in silico Virtual Screening (VS) of selected compounds were filtered according to their molecular weight and partition coefficient; a molecular weight of less than 500 and a partitioning coefficient (log P) of less than 5 filtering is applied.Result: Here, we report the screening of four compounds that have showed maximum binding affinity against Leptin receptor, obtained through the ZINC database. A VS approach coupled with docking energies illustrated that Pranlukast could be potential stimulator compounds for targeting Leptin receptor.Conclusion: We proposed that Pranlukast may be more potent Leptin receptor stimulator analogue based on the binding energy values. Further work can be extended to study the receptor ligand interactions experimentally and evaluation of their biological activity would help in designing novel therapeutic lead for the management of obesity disorders.
Highlights
The conclusion of the human genome project has given rise to an increase in number of novel therapeutic targets for drug discovery
We proposed that Pranlukast may be more potent Leptin receptor stimulator analogue based on the binding energy values
Further work can be extended to study the receptor ligand interactions experimentally and evaluation of their biological activity would help in designing novel therapeutic lead for the management of obesity disorders
Summary
The conclusion of the human genome project has given rise to an increase in number of novel therapeutic targets for drug discovery. High-throughput protein purification, crystallography and nuclear magnetic resonance spectroscopy techniques have been advanced and contributed to many structural details of proteins and protein–ligand complexes. These progresses let the computational strategies to permeate all aspects of drug discovery nowadays [1,2,3,4,5], such as the VS techniques [6] for hit identification and approaches for lead optimization. Whereas the BMI is defined as the weight in kilograms divided by the height in meters squared (kg/m2), is the most commonly used measure of obesity due to its low cost and easiness. Leptin is secreted by adipocytes, transported into the brain and binds to its receptor in the hypothalamus, and activates JAK-STAT3, leading to increase in “anorexigenic peptides” which normally inhibit food consumption and reduce weight
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