Biopharmaceutics and Biologic Drugs

Free fatty-acid receptor 1, is a G-protein-coupled receptor that binds long chain free fatty acids to enhance glucose-dependent insulin secretion and are therefore viable targets for diabetes and metabolic disorders. In the course of the research work, QSAR study, Pharmacophore generation, Molecular Docking, in-silico ADME studies and synthesis was performed to explore the molecular determinants responsible for the agonist action at GPR40. Th e generation of ligand & structure based pharmacophore using the standard tools within Catalyst from diff erent training sets consisted of Hydrophobic, Hydrogen Bond Acceptor and Aromatic ring features as essential aspects. Th e most representative features were selected and included in

the pharmacophore model which was further validated and utilized as a query tool to search 3D databases. CoMFA, CoMSIA and HQSAR were performed on series of 3-aryl-3-ethoxypropanoic acid derivatives to build 3D-QSAR models. Contour maps provided signifi cant insights which gave hints for the modifi cation required to design new molecules with improved biological activity. Molecular docking studies were carried out on designed molecules using Sybyl-X soft ware. Out of these the best Heteroaryl systems, specifi cally the fi ve membered pyrazole ring system was being explored and some of the virtual structures were synthetically explored, and 3-[3-(4-methoxyphenyl)-4-(phenoxymethyl)-1H-pyrazol-1-yl] acetic acid derivative class of compounds were synthesized taking into the account of sustainability and feasibility of the chemistry, which may act as a starting point for the in-house discovery program.