Identification of Key amino acid residues and structure based computational design of novel agonist for Farnesoid X Receptor (FXR): An In-Silico study

Abstract

Bile acid homeostasis is maintained by receptors and transporter present in the liver and the intestine. Farnesoid X receptor is one such nuclear receptor. It regulates the metabolism of biomolecules such as glucose and lipid. Farnesoid X receptor gets activated when excessive bile acid is produced by activating fibroblast like growth factor which further activates small heterodimer partner and this in turn will inhibit the transcription of CYP7A1 to maintain cholesterol homeostasis. Farnesoid X receptor turns out to be a demanding potent target for in-silico approaches. Agonist molecules of Farnesoid X receptor will bind to the allosteric sites of the receptor so that its activity gets enhanced. Comparative studies are done for Farnesoid X receptor agonist molecules where some of those have already been reported or are already in clinical trials. Amino acid interactions with receptor and ligands are studied to identify the key amino acid residues required for a ligand in order to bind specifically with Farnesoid X receptor. The newly developed pharmacophore has features that can help in designing of a novel drug which will act as an agonist molecule for Farnesoid X Receptor. Docking studies were carried out with libraries chosen from IBS Database and the best docked compounds were chosen. On the basis of the pharmacophore features and the top docked molecules, 55 novel quinoline-based derivatives were designed and only QC25 sufficed the docking parameters and the pharmacokinetic studies. Furthermore, the outcome of this study can be undertaken for MD simulation, synthesis, in-vitro and in-vivo analysis as well as nano-formulation studies for the potential activity.