Prediction of the interaction of HIV-1 integrase and its dicaffeoylquinic acid inhibitor through molecular modeling approach.
An essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1) is integration of the double-stranded retroviral DNA into the genome of the host cell. HIV-1 integrase, the enzyme that inserts the vital DNA into the host chromosome, is an attractive and rational target for anti-AIDS drug design because it is essential for HIV replication and there are no known counterparts in the host cell. Inhibitors of this enzyme have a great potential to complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. Natural products have provided a source of new drug candidates for anti-AIDS therapy. Dicaffeoylquinic acids, isolated from traditional medicinal plants, are a novel class of integrase inhibitors. These compounds are potent inhibitors of HIV-1 replication in cultured cell lines and catalytic activities of integrase in vitro. They are therefore promising compounds for developing new anti-AIDS drugs. To understand how the inhibitors work and therefore design more potent and specific inhibitors, we have used molecular modeling techniques to investigate the binding modes of 3,4-dicaffeoylquinic acid. Our computational modeling study demonstrated that the inhibitor of this compound on HIV integrase is likely to proceed by two different but equivalent mechanisms with one bound to the active site region of the enzyme and another docked into the binding pocket located on the other side of the catalytic site. Our study will be of help to design new pharmaceuticals for the treatment of AIDS.
Hu
Zengjian
Z
Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, DC 20059, USA. zhu@howard.edu
Chen
Dagang
D
Dong
Lanxiang
L
Southerland
W M
WM
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D019295:Computational Biology; D015195:Drug Design; D019427:HIV Integrase / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D019429:Integrase Inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D016662:Virus Integration / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology
D019429:Integrase Inhibitors; C472707:caffeoylquinic acid; D011801:Quinic Acid; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1