Research Articles

De novo design and in-silico studies of novel bis-arylpiperazine derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Vol. 1 No. 2 (2014) 22-27 Published July 28, 2014

934 Views352 Downloads1 Citations

PDF

Abstract

In the present study, we have designed some novel bisarylpiperazine derivatives as Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. Docking studies of the designed analogues were performed by molecular modeling software AutoDock 4.2 using HIV-1 Reverse Transcriptase (PDB ID: 1RT2) as receptor. Lipinskis Rule of Five (Ro5) parameters and toxicity parameters were predicted through online servers like Molinspiration and Osiris property explorer. Docking parameters such as binding free energy and predicted inhibitory constant (Ki) values of the designed analogues were compared with standard drugs Efavirenz and co-crystallized ligand TNK-651. Among the designed analogues, 1, 4, 8, 9, 12, 15, 27, 30, 37, 38, 39 and 43 showed significant and comparable binding free energy and predicted inhibitory constant values as that of standard drugs. These results indicate that, the designed analogues adopt a similar orientation and share the same binding mode as that of some of the classical Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) within the active site of Non-Nucleoside Inhibitory Binding Pocket (NNIBP) of HIV-1 reverse transcriptase.

References

  1. Gellis, A.; Dumtre, A.; Lanzada, G.; Hutter, S.; Ollivier, E.; Vanelle, P.; Azas, N., Preparation and antiprotozoal evaluation of promising ?-carboline alkaloids. Biomed Pharmacotherapy 2012, 66, 339-347.
  2. http://dx.doi.org/10.1016/j.biopha.2011.12.006 DOI: https://doi.org/10.1016/j.biopha.2011.12.006
  3. Li, D.; Zhan, P.; De Clercq, E.; Liu, X., Strategies for the Design of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Lessons from the Development of Seven Representative Paradigms. J Med Chem 2012, 55, 3595-3613.
  4. http://dx.doi.org/10.1021/jm200990c DOI: https://doi.org/10.1021/jm200990c
  5. de Bthune, M.-P., Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: A review of the last 20 years (19892009). Antivir Res 2010, 85, 75-90.
  6. http://dx.doi.org/10.1016/j.antiviral.2009.09.008 DOI: https://doi.org/10.1016/j.antiviral.2009.09.008
  7. Chong, P.; Sebahar, P.; Youngman, M.; Garrido, D.; Zhang, H.; Stewart, E. L.; Nolte, R. T.; Wang, L.; Ferris, R. G.; Edelstein, M.; Weaver, K.; Mathis, A.; Peat, A., Rational Design of Potent Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. J Med Chem 2012, 55, 10601-10609.
  8. http://dx.doi.org/10.1021/jm301294g DOI: https://doi.org/10.1021/jm301294g
  9. Penta, A.; Chander, S.; Ganguly, S.; Murugesan, S., De novo design and in-silico studies of novel 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid derivatives as HIV-1 reverse transcriptase inhibitors. Med Chem Res 2014, 1-9.
  10. http://dx.doi.org/10.1007/s00044-014-0945-9 DOI: https://doi.org/10.1007/s00044-014-0945-9
  11. Masanda, V. H.; Patila, K. N.; Jawarkar, R. D.; Haddac, T. B.; Youssoufi, M. H.; Alafeefyd, A. A., Exploring interactions of 2-Amino-6-arylsulfonylbenzonitrile derivatives as nonnucleoside reverse transcriptase inhibitors of HIV-1 using docking studies. J Comput Method Mol Design 2011, 1, 39-48.
  12. Genin, M. J.; Poel, T. J.; Yagi, Y.; Biles, C.; Althaus, I.; Keiser, B. J.; Kopta, L. A.; Friis, J. M.; Reusser, F.; Adams, W. J.; Voorman, R. L.; Thomas, R. C.; Romero, D. L., Synthesis and Bioactivity of Novel Bis(heteroaryl)piperazine (BHAP) Reverse Transcriptase Inhibitors: Structure?Activity Relationships and Increased Metabolic Stability of Novel Substituted Pyridine Analogs. J Med Chem 1996, 39, 5267-5275.
  13. http://dx.doi.org/10.1021/jm960269m DOI: https://doi.org/10.1021/jm960269m
  14. Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; et, a., Discovery, Synthesis, and Bioactivity of Bis(heteroaryl)piperazines. 1. A Novel Class of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors. J Med Chem 1994, 37, 999-1014.
  15. http://dx.doi.org/10.1021/jm00033a018 DOI: https://doi.org/10.1021/jm00033a018
  16. Janssen, P. A. J.; Lewi, P. J.; Arnold, E.; Daeyaert, F.; de Jonge, M.; Heeres, J.; Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.; Andries, K.; de Bthune, M.-P.; Pauwels, R.; Das, K.; Clark, A. D.; Frenkel, Y. V.; Hughes, S. H.; Medaer, B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.; Williams, P.; Stoffels, P., In Search of a Novel Anti-HIV Drug: Multidisciplinary Coordination in the Discovery of 4-[[4-[[4-[(1E)-2-Cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, Rilpivirine). J Med Chem 2004, 48, 1901-1909.
  17. http://dx.doi.org/10.1021/jm040840e DOI: https://doi.org/10.1021/jm040840e
  18. Ishida, J.; Wang, H.-K.; Oyama, M.; Cosentino, M. L.; Hu, C.-Q.; Lee, K.-H., Anti-AIDS Agents. 46.1 Anti-HIV Activity of Harman, an Anti-HIV Principle from Symplocos setchuensis, and Its Derivatives. J Nat Prod 2001, 64, 958-960.
  19. http://dx.doi.org/10.1021/np0101189 DOI: https://doi.org/10.1021/np0101189
  20. Rao, K. V.; Kasanah, N.; Wahyuono, S.; Tekwani, B. L.; Schinazi, R. F.; Hamann, M. T., Three New Manzamine Alkaloids from a Common Indonesian Sponge and Their Activity against Infectious and Tropical Parasitic Diseases?. J Nat Prod 2004, 67, 1314-1318.
  21. http://dx.doi.org/10.1021/np0400095 DOI: https://doi.org/10.1021/np0400095
  22. Adachi, J.; Mizoi, Y.; Naito, T.; Ogawa, Y.; Uetani, Y.; Ninomiya, I., Identification of Tetrahydro-?-carboline-3-carboxylic Acid in Foodstuffs, Human Urine and Human Milk. J Nutr 1991, 121, 646-652. DOI: https://doi.org/10.1093/jn/121.5.646
  23. Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G., Manzamine A, a novel antitumor alkaloid from a sponge. J Am Chem Soc 1986, 108, 6404-6405.
  24. http://dx.doi.org/10.1021/ja00280a055 DOI: https://doi.org/10.1021/ja00280a055
  25. Zhao, M.; Bi, L.; Bi, W.; Wang, C.; Yang, Z.; Ju, J.; Peng, S., Synthesis of new class dipeptide analogues with improved permeability and antithrombotic activity. Bioorg Med Chem 2006, 14, 4761-4774.
  26. http://dx.doi.org/10.1016/j.bmc.2006.03.026 DOI: https://doi.org/10.1016/j.bmc.2006.03.026
  27. Won, T. H.; Jeon, J.-e.; Lee, S.-H.; Rho, B. J.; Oh, K.-B.; Shin, J., Beta-carboline alkaloids derived from the ascidian Synoicum sp. Bioorg Med Chem 2012, 20, 4082-4087.
  28. http://dx.doi.org/10.1016/j.bmc.2012.05.002 DOI: https://doi.org/10.1016/j.bmc.2012.05.002
  29. Takasu, K.; Shimogama, T.; Saiin, C.; Kim, H.-S.; Wataya, Y.; Ihara, M., ?-Delocalized ?-carbolinium cations as potential antimalarials. Bioorg Med Chem Lett 2004, 14, 1689-1692.
  30. http://dx.doi.org/10.1016/j.bmcl.2004.01.055 DOI: https://doi.org/10.1016/j.bmcl.2004.01.055
  31. Gohil, V. M.; Brahmbhatt, K. G.; Loiseau, P. M.; Bhutani, K. K., Synthesis and anti-leishmanial activity of 1-aryl-?-carboline derivatives against Leishmania donovani. Bioorg Med Chem Lett 2012, 22, 3905-3907.
  32. http://dx.doi.org/10.1016/j.bmcl.2012.04.115 DOI: https://doi.org/10.1016/j.bmcl.2012.04.115
  33. Bonazzi, S.; Barbaras, D.; Patiny, L.; Scopelliti, R.; Schneider, P.; Cole, S. T.; Kaiser, M.; Brun, R.; Gademann, K., Antimalarial and antitubercular nostocarboline and eudistomin derivatives: Synthesis, in vitro and in vivo biological evaluation. Bioorg Med Chem 2010, 18, 1464-1476.
  34. http://dx.doi.org/10.1016/j.bmc.2010.01.013 DOI: https://doi.org/10.1016/j.bmc.2010.01.013
  35. Wang, Y.-H.; Tang, J.-G.; Wang, R.-R.; Yang, L.-M.; Dong, Z.-J.; Du, L.; Shen, X.; Liu, J.-K.; Zheng, Y.-T., Flazinamide, a novel ?-carboline compound with anti-HIV actions. Biochem Biophys Res Comm 2007, 355, 1091-1095.
  36. http://dx.doi.org/10.1016/j.bbrc.2007.02.081 DOI: https://doi.org/10.1016/j.bbrc.2007.02.081
  37. Brahmbhatt, K. G.; Ahmed, N.; Sabde, S.; Mitra, D.; Singh, I. P.; Bhutani, K. K., Synthesis and evaluation of ?-carboline derivatives as inhibitors of human immunodeficiency virus. Bioorg Med Chem Lett 2010, 20, 4416-4419.
  38. http://dx.doi.org/10.1016/j.bmcl.2010.06.052 DOI: https://doi.org/10.1016/j.bmcl.2010.06.052
  39. Hopkins, A. L.; Ren, J.; Esnouf, R. M.; Willcox, B. E.; Jones, E. Y.; Ross, C.; Miyasaka, T.; Walker, R. T.; Tanaka, H.; Stammers, D. K.; Stuart, D. I., Complexes of HIV-1 Reverse Transcriptase with Inhibitors of the HEPT Series Reveal Conformational Changes Relevant to the Design of Potent Non-Nucleoside Inhibitors. J Med Chem 1996, 39, 1589-1600.
  40. http://dx.doi.org/10.1021/jm960056x DOI: https://doi.org/10.1021/jm960056x
  41. Schttelkopf, W.; Aalten, D. M. F. v., PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr 2004, D66, 13551363.
  42. http://dx.doi.org/10.1107/S0907444904011679 DOI: https://doi.org/10.1107/S0907444904011679
  43. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D., Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J Med Chem 2002, 45, 2615-2623.
  44. http://dx.doi.org/10.1021/jm020017n DOI: https://doi.org/10.1021/jm020017n
  45. Verma, R. K.; Prajapati, V. K.; Verma, G. K.; Chakraborty, D.; Sundar, S.; Rai, M.; Dubey, V. K.; Singh, M. S., Molecular Docking and in Vitro Antileishmanial Evaluation of Chromene-2-thione Analogues. ACS Med Chem Lett 2012, 3, 243-247.
  46. http://dx.doi.org/10.1021/ml200280r DOI: https://doi.org/10.1021/ml200280r

Author information

  • Ashok Yadav

    Department of Pharmacy, BITS-Pilani

  • Subhash Chander

    BITS Pilani

  • Hiren Lathiya

    BITS Pilani

  • Hardik Sharma

    BITS Pilani

  • Kriti Goyal

    BITS Pilani

  • Murugesan Sankaranarayanan

    BITS Pilani

Rights and permissions

Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.

About this article

Cite this article

(1)
Yadav, A.; Chander, S.; Lathiya, H.; Sharma, H.; Goyal, K.; Sankaranarayanan, M. De Novo Design and in-Silico Studies of Novel Bis-Arylpiperazine Derivatives As Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. J Pharm Chem 2014, 1 (2), 22-27. https://doi.org/10.14805/jphchem.2014.art10.
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver

Download Citation

Endnote/Zotero/Mendeley (RIS) BibTeX
Received
April 1, 2014
Published
July 28, 2014
Section
Research Articles
Pages
22-27

Keywords

  • AIDS
  • HIV-1 Reverse Transcriptase
  • molecular docking
  • molecular properties
  • AutoDock
  • ?-carboline

Most read articles by the same author(s)