Structure-Based Design, Synthesis And Screening Of CCR5 Antagonists As HIV-1 Entry Inhibitors

Since the AIDS (Acquired Immune Deficiency Syndrome) was confirmed by the US Center for Disease Control and Prevention (CDC) in June 1981, AIDS has spread worldwide and greatly threatened global public health and social, economic and political stability. In China the number of HIV-infected people is raised continuously and already came to 700,000 in 2007. Therefore the prevention and treatment of AIDS is an important problem currently for our country. The research of medicine against AIDS has attracted enormous attention and among them the research of HIV entry inhibitor displays an important significance.The recently discovered chemokine receptor CCR5, a primary co-receptor essential for HIV recognition and entry into cell, is a cell surface seven-transmembrane G-protein coupled receptor. CCR5 binds to the complex of gp120 with CD4 and promote HIV-1 to entry. CCR5 has been identified as a potential new target for the treatment of HIV-1 infection and many pharmaceutical companies have searched for CCR5 antagonist to block the HIV-CCR5 interaction. The first anti-HIV drug targeting CCR5 - maraviroc (brand name: Selzentry) developed by Pfizer Inc. was recently approved for clinical use by the Food and Drug Administration (FDA) of the United States.Since no experimentally determined three-dimensional CCR structure is currently available, we modeled the structure of CCR5 based on the structure of 1U19A protein of bovine rhodopsin. We docked the inhibitor to the modeled protein, and gained the reasonable complex structure using the flexible docking method. Based on the structure of CCR5 and the interactive characteristics of ligands with CCR5, a novel virtual library of CCR5 antagonists was constructed in a combinatorial strategy and virtual screened by DOCK 4.0 program. On the basis of the score of virtual screening the compounds with high scores were chosen for synthesis.TAK-779 and 44 novel compounds have been synthesized whose structures were confirmed by MS and 1H-NMR method. These compounds were screened the anti-HIV activity and cytotoxicity in TZM-bl cells. TAK-779 was used as reference agonists. The results of in vitro assay indicated that 6 compounds have good anti-HIV activity. LCCpro and LOYisop show maximum efficacy comparable to that of TAK-779, which indicated that these compounds could be used as leads for further development.The structure-activity relationship of target compounds was investigated by CoMFA according to the biological screening.