Keywords
HIV-1 Reverse Transcriptase
molecular docking
molecular properties
AutoDock
?-carboline
How to Cite
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
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.
http://dx.doi.org/10.1016/j.biopha.2011.12.006
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.
http://dx.doi.org/10.1021/jm200990c
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.
http://dx.doi.org/10.1016/j.antiviral.2009.09.008
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.
http://dx.doi.org/10.1021/jm301294g
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.
http://dx.doi.org/10.1007/s00044-014-0945-9
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.
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.
http://dx.doi.org/10.1021/jm960269m
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.
http://dx.doi.org/10.1021/jm00033a018
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.
http://dx.doi.org/10.1021/jm040840e
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.
http://dx.doi.org/10.1021/np0101189
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.
http://dx.doi.org/10.1021/np0400095
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.
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.
http://dx.doi.org/10.1021/ja00280a055
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.
http://dx.doi.org/10.1016/j.bmc.2006.03.026
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.
http://dx.doi.org/10.1016/j.bmc.2012.05.002
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.
http://dx.doi.org/10.1016/j.bmcl.2004.01.055
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.
http://dx.doi.org/10.1016/j.bmcl.2012.04.115
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.
http://dx.doi.org/10.1016/j.bmc.2010.01.013
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.
http://dx.doi.org/10.1016/j.bbrc.2007.02.081
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.
http://dx.doi.org/10.1016/j.bmcl.2010.06.052
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.
http://dx.doi.org/10.1021/jm960056x
Schttelkopf, W.; Aalten, D. M. F. v., PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr 2004, D66, 13551363.
http://dx.doi.org/10.1107/S0907444904011679
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.
http://dx.doi.org/10.1021/jm020017n
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.
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