Computational design of novel cyclic urea as HIV-1 protease inhibitor

Abstract

A series of novel cyclic urea molecules 5,6-dihydroxy-1,3-diazepane-2,4,7-trione as HIV-1 protease inhibitors were designed using computational techniques. The designed molecules were compared with the known cyclic urea molecules by performing docking studies, calculating their ADME (Absorption, Distribution, Metabolism, and Excretion) properties and protein ligand interaction energy. These novel molecules were designed by substituting the P 1 /P 1 positions (4 th and 7 th position of 1, 3-diazepan-2-one) with double bonded oxygens. This reduces the molecular weight and increases the bioavailability, indicating better ADME properties. The docking studies showed good binding affinity towards HIV-1 protease. The biological activity of these inhibitors were predicted by a model equation generated by the regression analysis between biological activity (log 1/K i ) of known inhibitors and their protein ligand interaction energy. The synthetic studies are in progress.

Prediction of kinase-inhibitor binding affinity using energetic parameters

“…These observations are reflected in the interaction energy contributions of our present analysis. The protein-ligand interaction energies obtained using PEARLS server has been used in other studies on inhibitor discovery such as HIV-1 protease [ 39 ] and ribonuclease A inhibitors [ 40 ] to predict the binding affinity values using regression analysis. Log P, remains the main deterministic factor for the ligand’s affinity for the protein active site with reference to the surrounding solvent environment [ 41 ].…”