Molecular Modeling Studies and ADME Screening on HIV-1 Integrase Inhibitors as Anti-Viral Agents

Author(s): D. Velmurugan, Sibi Narayanan

Human immunodeficiency virus (HIV) is a lentivirus, a member of the retrovirus family, which leads to acquired immunodeficiency syndrome (AIDS). HIV is present as both free virus particles and virus within infected immune cells. Integration of viral DNA into the host chromosome is the key process in the HIV replication cycle and therefore Integrase has served as an attractive target for antivirals. HIV-1 Integrase (HIV-1 IN) is an essential enzyme in the life cycle of the virus, responsible for catalyzing the insertion of the viral genome into the host cell chromosome and it provides an attractive target for antiviral drug design. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection. Raltegravir, also known as Isentress and MK-0518, is a well known integrase inhibitor. This prevents the virus from making new copies of HIV. Structures similar to this compound were identified and molecular modeling studies has been performed with HIV-1 IN as target molecule using Schrödinger Suite 2007. PASS (prediction of activity spectra for substances) prediction of the compounds was carried out and all compounds exhibited anti-viral activity. These compounds show favorable interactions with the amino acid residues and the metal ion (Mg2+) at the active site of HIV-1 IN thereby substantiating their proven efficacy as anti-viral compounds. Further, their ADME (Absorption, Digestion, Metabolism and Excretion) screening was also carried out in order to check their potency to be used for second-generation drug development. The work demonstrates that molecular modeling, activity prediction and screening of the compounds for their subsequent ADME properties is a promising approach to predict the binding activity of compounds to the receptor.

HIV, HIV-1 IN, antiviral, raltegravir, Schrödinger Suite 2007, PASS, ADME

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