Theoretical Study of Lamivudine Derivatives Invoking DFT based Descriptors

Theoretical Study of Lamivudine Derivatives Invoking DFT based Descriptors

Tanmoy Chakraborty, Seema Dhail
DOI: 10.4018/IJCCE.2015070103
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Recently Maria S. Gualdesi et al., have reported about bioactive lamivudine and its carbonate derivatives with proved activity against human immunodeficiency disease (anti-HIV) and hepatitis B viruses (anti-HBV) respectively in simulated gastric and intestinal fluids samples. This is one of the simplest, sensitive, accurate and precise assays for determining all the compounds which are readily adaptable for routine use in clinical laboratories. Employing simple chromatographic technique, they have lucidly explained the kinetic and stability features of lamivudine and its carbonate derivatives. But a theoretical quantum mechanical study of aforesaid compounds is yet to explore. In this report, the authors have made a correlation between experimental properties of lamivudine derivatives with their theoretical counterparts. They have invoked DFT based global and local descriptors to explore the effect of substituents on activity and mechanistic pathway of instant compounds respectively. Their computed data reveals a hand to hand relationship between experimental and theoretical parameters. Finally, a QSAR model has been proposed in terms of DFT based global descriptors.
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According to recent report provided by the World Health Organization (WHO), Acquired Immuno Deficiency Disease (AIDS) and Hepatitis B are rapidly emerging diseases over worldwide. Human immunodeficiency virus (HIV), mainly responsible for AIDS, is categorized under lentivirus which is slowly replicating retrovirus. Lentivirus badly infects the vital cells of human immune system causing progressive failure of the immune system and allows various life-threatening opportunistic infections and cancers to thrive.

Similarly, Hepatitis B Virus (HBV) is also a life-threatening virus, having potency to infect the liver of a human body directly. According to the current statistics of Centers for Disease Control and Prevention (CDC), the estimated number of people suffering from HIV infection is around 1,144,500. The mentioned number also includes 180,900 (15.8%) who are totally unaware of their infection (2013).

Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are blood borne viruses transmitted primarily through sexual contact and injection drug use. Because of these shared modes of transmission, a high proportion of adults at risk for HIV infection are also at risk for HBV infection. HIV-positive persons who become infected with Hepatitis B virus (HBV) are at increased risk for developing chronic HBV infection and should be tested. In addition, persons who are co-infected with HIV and HBV can have serious medical complications, including an increased risk for liver-related morbidity and mortality. To prevent HBV infection in HIV-infected persons, the Advisory Committee on Immunization Practices recommends universal Hepatitis B vaccination of susceptible patients with HIV/AIDS.

Maria S. Gualdesi et al., seven novel derivatives of lamivudine with proved activity against human immunodeficiency disease (anti-HIV) and hepatitis B viruses (anti-HBV) activity in simulated gastric and intestinal fluids are developed and validated (2013). In their research they optimized the method involving C18 column, which is simple, sensitive, accurate and precise assay for determining all the compounds and readily adaptable for routine use in clinical laboratories.

Lamivudine (2′,3′-dideoxy-3′-thiacytidine, commonly called 3TC) is a potent nucleoside analog reverse transcriptase inhibitor (nRTI). Lamivudine is an analogue of cytidine. It can inhibit both types (1 and 2) of HIV reverse transcriptase and also the reverse transcriptase of hepatitis B. It is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. Lamivudine is administered orally, and it is rapidly absorbed with a bio-availability of over 80%. Some research suggests that lamivudine can cross the blood–brain barrier. Lamivudine is often given in combination with zidovudine, with which it is highly synergistic. Lamivudine treatment has been shown to restore zidovudine sensitivity of previously resistant HIV. Lamivudine showed no evidence of carcinogenicity or mutagenicity in in vivo studies in mice and rats at doses from 10 to 58 times those used in humans (Gualdesi et al., 2013).

In the present work, we have tried to make a correlation between the percentage of degradation (3h) of 3TC derivatives at 37°C in intestinal fluid (SIF) of lamivudine derivatives with their global and as well as local quantum mechanical descriptors. Further using local density descriptors, we have tried to identify the most reactive site in the drug molecules. Multi linear regression analyses have been also used for making QSAR models in terms of computed global reactivity descriptors and experimental activity of lamivudine derivatives.

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