In silico approaches to explore structure of new GPR 119 agonists for treatment of type 2 diabetes mellitus

Abstract

The G protein coupled receptor 119 is an exciting and promising target for the treatment of type 2 diabetes mellitus. In this study, three dimensional quantitative structure activity relationships i.e. a comparative molecular field analysis and comparative molecular field analysis region focusing have been carried out on a novel series of G protein coupled receptor 119 agonists. A quality pharmacophore model was built by Hip-Hop algorithm. The best pharmacophore model indicated which feature of hydrogen-bond acceptor and hydrophobic existed around active compounds. As the quality of the pharmacophore model is satisfactory, it was utilized to search the ZINC database for a virtual screening task. The obtained compounds subjected to Lipinski filter at first, were docked with Gold algorithm to discover potent hits. The energy difference between the highest occupied molecular orbital and lowest unoccupied molecular orbital (“gap”) implies high reactivity of the most active molecule in the active site of protein. In addition, the molecular electrostatic potential energy at density functional theory level confirms the results from molecular docking. In silico absorption, distribution, metabolism, and excretion and toxicity risk assessment analysis were carried out on the seven hits with the highest Gold score fitness. Six of the new hits from virtual screening had diverse structures and are reported as new scaffold candidates for G protein coupled receptor 119 agonists.