A BATTLE AGAINST AIDS: NEW PYRAZOLE KEY TO AN OLDER LOCK-REVERSE TRANSCRIPTASE
DOI:
https://doi.org/10.22159/ijpps.2016v8i11.12634Keywords:
HIV, Pyrazole analogs, Docking study, ADME-TAbstract
Objective: The reason for the failure of most of the anti-HIV drugs are their poor pharmacokinetics, the poor risk to benefit ratio and the drug resistance. With the objective of developing newer pyrazole scaffolds for effective treatment of HIV, binding mode analysis of designing ligands with the HIV-1RT protein and prediction of key ADME and toxicity parameters of the compounds was in an area of interest.
Methods: In this study, molecular docking studies and ADME-T studies were carried out in designing of some novel pyrazole analogs. The protein (PDB ID: 1RT2) was prepared using the Protein Preparation Wizard (Schrodinger Glide 5.0). ADME parameters calculated by QikProp 3.0v and toxicity of designed analogs checked by using two different online software's namely Lazar and protox.
Results: Most of the designed pyrazole analogs have good oral absorption as well as good binding affinity towards HIV-1 reverse transcriptase.
Conclusion: Finally total 5 analogs (SGS-2, 3, 12, 13 and 14) from the 14 designed leads were found to be best on the basis of molecular docking and ADME-T studies.
Downloads
References
Hindmarsh P, Leis J. Retroviral DNA integration. Microbiol Mol Biol Rev 1999;63:836-43.
Ganguly S, Murugesan S, Prasanthi N, Alptürk O, Herman B, Sluis-Cremer N. Synthesis and anti-HIV-1 activity of a novel series of aminoimidazole analogs. Lett Drug Des Discovery 2010;7:318-23.
Himmel DM, Sarafianos SG, Dharmasena S, Hossain MM, McCoy-Simandle K, Ilina T, et al. HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site. ACS Chem Biol 2006;1:702-12.
Kohlstaedt LA, Wang J, Friedman J, Rice P, Steitz T. Crystal structure at 3.5 resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 1992;256:1783-90.
Sarafianos SG, Das K, Hughes SH, Arnold E. Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases. Curr Opin Struct Biol 2004;14:716–30.
Martins S, Ramos MJ, Fernandes PA. The current status of the NNRTI family of antiretrovirals used in the HAART regimen against HIV infection. Curr Med Chem 2008;15:1083-95.
Sweeney ZK, Klumpp K. Improving non-nucleoside reverse transcriptase Inhibitors for the ï¬rst-line treatment of HIV infection: the development pipeline and recent clinical data. Curr Opin Drug Discovery Dev 2008;11:458-70.
Daar ES. Emerging resistance proï¬les of newly approved antiretroviral drugs. Topics HIV Med 2007;16:110-6.
Sriram D, Bal TR, Yogeeswari P. Newer aminopyrimidine imino isatin analogues as non-nucleoside HIV-1 reverse transcriptase inhibitors for HIV and other opportunistic infections of AIDS: design, synthesis and biological evaluation. Il Farmaco 2005; 60:377-84.
Schaefer W, Friebe WG, Leinert H, Mertens A, Poll T, Von der Saal W, et al. Non-nucleoside inhibitors of HIV-1 reverse transcriptase: molecular modeling and X-ray structure investigations. J Med Chem 1993;36:726-32.
Ragno R, Frasca S, Manetti F, Brizzi A, Massa S. HIV-reverse transcriptase inhibition: inclusion of ligand-induced fit by cross-docking studies. J Med Chem 2005;48:200-12.
Rostom SAF, El-Ashmawy IM, Abd El Razik HA, Badr MH, Ashour HMA. Design and synthesis of some thiazolyl and thiadiazolyl derivatives of antipyrine as a potential non-acidic anti-inflammatory analgesic and antimicrobial agents. Bioorg Med Chem 2009;17:882-95.
Zhang D, Wang G, Zhao G, Xu W, Huo L. Synthesis and cytotoxic activity of novel 3-(1H-indol-3-yl)-1H-pyrazole-5-carbo-hydrazide derivatives. Eur J Med Chem 2011;46:5868-77.
Kumar A, Jain S, Parle M, Jain N, Kumar P. 3-aryl-1-phenyl-1h-pyrazole derivatives as new multitarget directed ligands for the treatment of Alzheimer’s disease with acetylcholinesterase and Monoamine oxidase inhibitory properties. EXCLI J 2013; 12:1030-42.
Mowbray CE, Burt C, Corbau R, Gayton S, Hawes M, Perros M, et al. Pyrazole NNRTIs 4:Selection of UK-453 061 (lersivirine) as a development candidate. Bioorg Med Chem Lett 2009;19:5857-60.
Biopharmaceutical research Industry. Available from: http:// www.phrma.org/sites/default/files/pdf/2015_phrma_profile.pdf. [Last accessed 15 Dec 2015].
Lipinski CA. Lead-and drug-like compounds: the rule-of-five revolution. Drug Discovery Today Technol 2004;1:337-41.
Swastika G, Geeta Y. Molecular docking studies of novel benzimidazole analogs as HIV-1-RT inhibitors with broad-spectrum chemotherapeutic properties. Int J Drug Des Discovery 2013;4:1193-13.
Maunz A, Gütlein M, Rautenberg M, Vorgrimmler D, Gebele D, Helma C. Lazar: a modular predictive toxicology framework. Front Pharmacol 2013;4:1-0.
Helma C. Lazy structure-activity relationships (lazar) for the prediction of rodent carcinogenicity and Salmonella mutagenicity. Mol Diversity 2006;10:147-58.
Drwal MN, Banerjee P, Dunkel M, Wettig MR, Preissner R. ProTox: a web server for the in silico prediction of oral rodent toxicity. Nucleic Acids Res 2014;42:W53-8.
Published
How to Cite
Issue
Section
