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

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

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Author(s)

Author(s): D. Velmurugan, Sibi Narayanan

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912 1462 1-12 Volume 2 - May 2013

Abstract

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.

Keywords

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

References

  1. Asante-Appiah, E., Skalka, A.M. (1999). HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv. Virus Res., 52, 351-369. http://dx.doi.org/10.1016/S0065-3527(08)60306-1
  2. Chen, J.C., Krucinski, J., Miercke, J., Finer Moore, J.S., Tang, A.H., Leavitt, A.M., Stroud, R.M. (2000). Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding. Proc. Natl. Acad. Sci. USA, 97, 8233-8238. http://dx.doi.org/10.1073/pnas.150220297
  3. Chiu, T.K., Davies, D.R. (2004). Structure and function of HIV-1 integrase. Curr. Top. Med. Chem., 4, 965-977. http://dx.doi.org/10.2174/1568026043388547
  4. Christoph, A.S., Haihong, N., McCammon, J.A. (2000). HIV-1 Integrase Inhibitor Interactions at the Active Site: Prediction of Binding Modes Unaffected by Crystal Packing. J. Am. Chem., 122, 6136-6137. http://dx.doi.org/10.1021/ja001152x
  5. De Clercq, E. (2004). Antiviral drugs in current clinical use. J. Clin. Virol., 30, 115-133. http://dx.doi.org/10.1016/j.jcv.2004.02.009
  6. De Clercq, E. (2005). New approaches toward anti-HIV chemotherapy. J. Med. Chem., 48, 1297-313. http://dx.doi.org/10.1021/jm040158k
  7. Dixon, J.S., Blaney, J.M. (1998). Designing Bioactive Molecules: Three-dimensional techniques and applications. Edited by Martin, Y.C., Willet, P., Washington. DC, American Chemical Society, 175-197
  8. Dyda, F., Hickman, A.B., Jenkins, T.M., Engelman, A., Craigie, R., Davies, D.R. (1999). Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases. Science, 266, 1981-1986. http://dx.doi.org/10.1126/science.7801124
  9. Eijkelenboom, A.P., Sprangers, R., Hard, K., Puras Lutzke, R.A., Plasterk, R.H., Boelens, R., Kaptein, R. (1999). Refined solution structure of the C-terminal DNA-binding domain of human immunovirus-1 integrase. Proteins, 36, 556-564. http://dx.doi.org/10.1002/(SICI)1097-0134(19990901)36:4<556::AID-PROT18>3.0.CO;2-6
  10. Engelman, A., Mizuuchi, K., Craigie, R. (1991). HIV-1 DNA integration: Mechanism of viral DNA cleavage and DNA strand transfer. Cell, 67, 1211-1221. http://dx.doi.org/10.1016/0092-8674(91)90297-C
  11. Esposito, D., Craigie, R. (1999). HIV integrase structure and function. Adv. Virus Res., 52, 319-333. http://dx.doi.org/10.1016/S0065-3527(08)60304-8
  12. Gerton, J.L., Brown, P.O. (1997). The Core Domain of HIV-1 Integrase Recognizes Key Features of Its DNA Substrates. The Journal of Biological Chemistry, 272, 25809-25815. http://dx.doi.org/10.1074/jbc.272.41.25809
  13. Goldgur, Y., Dyda, F., Hickman, A.B., Jenkins, T.M., Craigie, R., Davies, D.R. (1998). Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium. Proc. Natl. Acad. Sci. USA, 95, 9150-9154. http://dx.doi.org/10.1073/pnas.95.16.9150
  14. Goldur, Y., Craigie, R., Cohen, G.H., Fujiwara, T., Yoshinaga, T., Fujishita, T., Sugimoto, H., Endo, T., Murai, H., Davies, D.R. (1999). Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design. Proc. Natl. Acad. Sci. U. S. A., 96, 13040. http://dx.doi.org/10.1073/pnas.96.23.13040
  15. Greenwald, J., Le, V., Butler, S.L., Bushman, F.D., Choe, S. (1999). The mobility of an HIV-1 integrase active site loop is correlated with catalytic activity. Biochemistry, 38, 8892-8898. http://dx.doi.org/10.1021/bi9907173
  16. Hazuda, D.J., Felock, P., Witmer, M., Wolfe, A., Stillmock, K., Grobler, J.A., Espeseth, A., Gabyelski, L., Schleif, W., Blau, C., Miller, M.D. (2000). Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science, 287, 646-650. http://dx.doi.org/10.1126/science.287.5453.646
  17. Kuo, C.L., Assefa, H., Kamath, S., Brzozowoski, Z., Slawinski, J., Saczewski, F., Buolamwini, J.K., Neamati, N. (2004). Application of CoMFA and CoMSIA 3D-QSAR and Docking Studies in Optimization of Mercaptobenzenesulfonamides as HIV-1 Integrase Inhibitors. J. Med. Chem., 47, 385-399. http://dx.doi.org/10.1021/jm030378i
  18. Leroy, D., Kajava, A.V., Frei, C., Gasser, S.M. (2001). Analysis of etoposide binding to subdomains of human DNA topoisomerase IIa in the absence of DNA. Biochemistry, 40, 1624-1634. http://dx.doi.org/10.1021/bi0019141
  19. Lodi, P.J., Ernst, J.A., Kuszewski, A., Hickman, A.B., Engelman, A., Craigie, R., Chlore, G.M., Gronenborn, A.M. (1995). Solution structure of the DNA binding domain of HIV-1 integrase. Biochemistry, 34, 9826-9833. http://dx.doi.org/10.1021/bi00031a002
  20. Ni, H., Sotrifier, C.A., McCammon, J.A. (2001). Ordered water and ligand mobility in the HIV-1 integrase-5CITEP complex: A molecular dynamics study. J. Med. Chem., 44, 3043-3047. http://dx.doi.org/10.1021/jm010205y
  21. Smith, P.A., Sorich, M.J., Low, L.S.C., McKinnen, R.A., Miners, J.O. (2004). Towards integrated ADME prediction: past, present and future directions for modelling metabolism by UDP-glucuronosyltransferases. J. Mol. Graphics Modeling, 22, 507-517. http://dx.doi.org/10.1016/j.jmgm.2004.03.011
  22. ter Heine, R., Hillebrand, M.J.X., Rosing, H., van Gorp, E.C.M., Mulder, J.W., Beijnen, J.H., Huitema, A.D.R. (2009). Quantification of the HIV-integrase inhibitor raltegravir and detection of its main metabolite in human plasma, dried blood spots and peripheral blood mononuclear cell lysate by means of high-performance liquid chromatography tandem mass spectrometry. J. Pharm. Biomed. Analysis, 49, 451-458. http://dx.doi.org/10.1016/j.jpba.2008.11.025
  23. Vink, C., Oude Groeneger, A.M., Plasterk, R.H. (1993). Identification of the catalytic and DNA-binding region of the human immunodeficiency virus type 1 integrase protein. Nucleic Acids Res., 21, 1419-1425. http://dx.doi.org/10.1093/nar/21.6.1419
  24. Zheng, R., Jenkins, T.M., Craigie, R. (1996). Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity. Proc. Natl. Acad. Sci. U. S. A., 93, 13659. http://dx.doi.org/10.1073/pnas.93.24.13659

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International Journal of Sciences is Open Access Journal.
This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License.
Author(s) retain the copyrights of this article, though, publication rights are with Alkhaer Publications.

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