Comparing Inhibiting Activity of HIV-1 Protease between Indinavir and its Modifications Using Computational Approaches
Objectives: To develop a potent anti-HIV agent
Methods: In the present study, two candidate ligand compounds-Pridyl methyl piperazine with acetamide and Urea derivative were designed using Chemsketch, by replacing –OH group based on indinavir as reference molecule. Designed ligands were tested in silico individually with HIV-1 protease enzymes. Rigid docking approach was applied to both the compounds by using Autodock, and qualitative inspection of the results was carried out.
Findings: Compound Modified 2 containing functional group pyridyl methyl piperazine with acetamide in place of hydroxyl group, and compound Modified 1 having urea derivative in place of hydroxyl group has shown potential bindings with HIV-1 protease enzyme. The Modified 2 showed better interactions in rigid docking method with an average lowest binding energy of -3.87 kcal/mol towards HIV-1 protease enzyme as compared to Indinavir which showed -3.52 kcal/mol lowest binding energy. However, the Modified 1’ interactions were weak with an average lowest binding energy of +0.9 kcal/mol. In wake of the present work, it indicates that the compound Modified 2 which has been designed, has the tendency to interact with protease with efficient binding and emerges out as a potential candidate inhibitor of HIV-1 enzymes for further experimentation.
Application: Regardless of the drawbacks of chemical drugs such as its malignancy and lack of therapeutic effects, our study has shown that it is possible to produce more formidable potent anti-HIV agents.
- M.Nielsen, S.Pedersen, J.Kjems. Molecular strategies to inhibit HIV-1 replication. Retrovirology. 2005; 2(10), 1-20.
- E. Clercq. Toward improvement anti-HIV chemotherapy: therapeutic strategies for intervention with HIV-1 infections. Journal of Medicinal Chemistry.1998; 38, 2491-2517.
- A. Pani, A. G. Loi, M. Mura, T. Marceddu, P. La Colla, M. E. Marongiu. Targeting HIV: old and new players. Current Drug Targets-Infectious Disorders.2002; 2(1), 17-32.
- M. Coffin, H. Hughes, E. Varmus, P. Brown. Integration in retroviruses. ColdSpringHarbor Laboratory Press: New York, 1997.
- H. Pearl, A. Taylor. A structural model for the retroviral proteases. Nature. 1997; 329, 351-354.
- P. Darke, R. Nutt, S. Brady, V. Garsky, T. L. Ciccarone, P. Lumma, R. Freidinger, D. Veber, I. Sigal. HIV-1 protease specificity of peptide cleavage is sufficient for processing of gag and pol polyproteins. Biochemical andBiophysical Research Communications.1988; 156, 297-303.
- S. Oroszlan, R. Luftig. Retroviral proteinases. Currrent Topics in Microbiology Immunology.1990; 157, 153-185.
- F. Schinazi, I. Hernandez-Santiago, J. Hurwitz. Pharmacology of current and promising nucleosides for the treatment of human immunodeficiency viruses. Erratum Antiviral Res.2006; 71, 322-334.
- B. Young, D. Kuritzkes. Resistance to HIV-1 protease inhibitors. Infectious Disease andTherapy.2002; 25, 257-282.
- L. Bacheler. Resistance to non-nucleoside inhibitors of HIV-I reverse transcriptase. Drug Resistance Updates.1999; 2(1), 56-67.
- G. Barbaro, A. Scozzafava, A. Mastrolorenzo, C. Supuran. Highly active antiretroviral therapy: current state of the art, new agents and their pharmacological interactions useful for improving therapeutic outcome. Current Pharmaceutical Design.2005; 11, 1805-1843.
- K. Ghosh, D. Anderson. Tetrahydrofuran, tetrahydropyran, triazoles and related heterocyclic derivatives as HIV protease inhibitors. Future Medicinal Chemistry.2011;3(9), 1181-1197.
- D. Goodsell, J. Olson. Automated docking of substrates to proteins by simulated annealing. Proteins: Structure, Function, and Bioinformatics.1990; 8, 195-202.
- D. Goodsell, G. Morris, A. Olson. Automated docking of flexible ligands: Applications of AutoDock. Journal of Molecular Recognition.1996; 9, 831-835.
- Using AutoDock 4 and AutoDockVina with AutoDockTools: A Tutorial. http://autodock.scripps.edu/. Date accessed: 10/10/2015.
- G. Morris, S. Goodsell, S. Halliday, R. Huey, E. Hart, K. Belew, J. Olson. Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function.Journal of Computational Chemistry.1998; 19, 1639-1662.
- G. Morris, R. Huey, W. Lindstrom, F. Sanner, K. Belew, S. Goodsell, J. Olson. AutoDock4and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry.2009; 30, 2785-2791.
- M. Lazarova. Virtual screening-models, methods and software systems. International Scientific Conference Computer Science. 2008; 55-60.
- There are currently no refbacks.