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Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

In silico study on HIV-PRIs substructures to terminate proteolytic activity in HTLV

Human T-lymphotropic virus (HTLV) is RNA retrovirus, which is causing CD3+ and CD4+ T-cell type leukemia and demyelinating diseases, like tropical spastic myelopathy. The replicative stage of the virus is one of the critical stages for the development of the disease. At present, there are no approved therapeutic agents targeting HTLV. HTLV mechanism of malignant cell growth in adult T-cell leukemia (ATL) /lymphoma, and the HTLV-PR has been an attractive target for anti cancer drug design. In comparison to other retroviruses HTLV also encodes protease (PR) enzyme, which is essential for maturation. Both HIV and HTLV proteases shows high structural similarity but known inhibitors of HIV-PR are not able to inhibit the HTLV-PR, while comparing the binding pocket of both proteases, MET37 of HTLV showing repulsive role with known HIV inhibitors. Functional analysis of M37A mutation clearly shows that MET37 is highly important for the protease function. Available inhibitors were tested against the HTLV-PR binding pocket and failed to interact with MET37. Screening of similar libraries of known compounds provides better interactions with MET37 and further validation with in vivo and in vitro studies on these screened compounds will provide more strength in discovering potent inhibitor for HTLV-PR.

References

    Zhang M et al. (2008). Locking the two ends of tetrapeptidic HTLV-I protease inhibitors inside the enzyme. Bioorg Med Chem. 16(14):6880-90.

    Shuker S.B et al. (2003), Understanding HTLV-I protease. Chem. Biol, 10(5):373-80.

    Kadas J et al. (2004). Total chemical synthesis of human T-cell leukemia virus type 1 (HTLV-1) protease via native chemical ligation. Biol Chem, 279, 27148-27157.

    Das D et al. (2009). Prediction of potency of protease inhibitors using free energy simulations with polarizable quantum mechanics-based ligand charges and a hybrid water model. J Chem Inf Model, 49, 2851-2862.


Poonam Singh 1*
Sanjeev Kumar Singh2
Chandrabose Selvaraj 2
Rama Kant Singh 1

1Toxicology Division
Central Drug Research Institute
Lucknow-226 001
Uttar Pradesh, India 2Computer Aided Drug Design and Molecular Modeling Lab
Department of Bioinformatics
Alagappa University
Karaikudi-630003
Tamilnadu, India

*Ph: +91-522-2612411
Fx: +91-522-2623405
poonamsinghcdri@gmail.com