The Pharmacophore Model Of Integrase Inhibitors And Design And Synthesis Of Aromatic Diketones Compounds

Acquired immune deficiency syndrome (AIDS) resulted by HIV was infectiousdisease that seriously threatened human health. Integrase plays an important role inthe retroviral life cycle. So it is a rational target for treating HIV infection and preventing AIDS.Because the crystal structure of HIV-1integrase was not reported and drugdesign based on ligand was the appropriate way to find new integrase inhibitorsquickly. A3D pharmacophore model was derived having quantitative predictiveability in terms of activity based on a training set of diketo-like acid HIV-1integrasestrand-transfer inhibitors, using3DQSAR Pharmacophore Generation module inDiscovery studio3.1. The optimal pharmacophore model1has four features, includesthree hydrogen bond acceptors, one hydrophobic feature, which has the highestcorrelation coefficient as0.973. It was validated using external test set and Fischer’srandomization method. The result showed it was a reasonable and effectivepharmacophore model, used as a3D query for virtual screening to retrieve potentialinhibitors from Maybridge to find better lead compounds as anti-HIV integrase.Integrase as the target drug development is hot in the current HIV drug research,and diketone acid (DKA) is the most successful kind of integrase inhibitors. Based onthe combination of the two ketone acid as a major activity ligand with intergraseenzyme, we considered the design and synthesis the Desmosdumotin D analogueswith as the main active group. And according to the combination principles in thedrug design, we design new compounds as the coffee acid effective group connectedto the other side of1,3-diketone, in hope to increase the activity of anti-HIV integrase.The best pharmacophore model produced in the second chapter predicts biologicalactivity of the target compounds. According to the results of molecular docking, thetarget compounds share a similar binding model with5-CITEP combined with IN,though they have no common scaffold. This suggests both of the inhibitors may havea similar inhibitory mechanism. Finally, the results show that the target compoundshave certain degree activity as integrase inhibitors, through the MAGI method.