Novel nitrogen-containing heterocyclic compounds in GPR109A as an anti-hyperlipidemic: Homology modeling, docking, dynamic simulation studies

Abstract

Niacin or nicotinic acid therapy leads to reduction of the level of Low-density Lipoprotein cholesterol (20-40%) with significant elevation of High-Density Lipopreoin cholesterol level (20-35%). From research, it was said that Nicotinic acid might exert its positive action by activating the G-protein-coupled receptor (GPCR) which is found on adipocytes. GPR109A (family of GPCR) receptor was important for nicotinic acid (niacin) for its anti-lipolytic effects. As GPR109A is a targeted receptor for the treatment of dyslipidemia, its structural analysis needs to be elucidated. But the Protein 3D structure of target was not available at Protein Data Bank (PDB), so we have generated its structure through homology modeling and validation was carried out. Screening of top lead molecules with the help of various computational approaches like molecular-docking and molecular dynamic (MD) simulations studies with different online tools were carried out. The docking results showed that the lead compound 2B [(R)-methyl 2-(2-(1H-indol-3-yl) acetamido)-3-(1H-indol-3-yl) propionate] revealed significant binding energy value (-30.54 kcal/mol) as that with the nicotinic acid which is a standard drug (-17.68 kcal/mol). In addition to that, Molecular-Dynamic (MD) simulations analysis proved that compound 2B has lesser variations throughout the simulation period as represented by the root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) graphs. Current in silico study describes the modeling of novel heterocyclic compounds as antihyperlipidemic drugs for the treatment of dyslipidemia. This study also describes a deeper idea about the structural information of the lead compound 2B and its entire molecular interactions against GPCR109A and provides a hypothetical guideline to utilize this compound as an antihyperlipidemic for the treatment of dyslipidemia.