Open Access Subscription Access
Open Access Subscription Access
In Silico Analysis of Novel Azetidinone Substituted Benzotriazole and Benzimidazole Derivatives as Plasmodium Falciparum Glutamate Dehydrogenase Inhibitors
NADP-dependent enzyme Glutamate dehydrogenase is responsible for the maintenance of reduced state in plasmodia. Chloroquine and Mefloquine inhibit glutamate dehydrogenase enzyme and also glutathione reductase like antioxidative enzyme and thioredoxin, inducing oxidative stress. Plasmodia can't survive in the highly oxidized medium. From a detailed study on the SAR of quinolines, a series of compounds were designed and developed using molecular docking, In silico analysis was done using SWISSADME online tool, and bioactivity prediction was performed using Molinspiration online tool. Among the all designed compounds, in the benzotriazole series, compound code 1(d) (-103.22kcal/mol), 1(e) (-102.05kcal/mol), and 1(b) (-100.78 kcal/mol) show good binding affinity. Whereas, in the benzimidazole series, compound code 2(f) (-104.98 kcal/mol), 2(b) (-104.86kcal/mol) and 2(g) (-104.08kcal/mol) shows good binding affinity. The performed research reveals that benzimidazole derivatives offer an advantage over benzotriazole moiety for binding affinity with the enzyme Plasmodium Falciparum glutamate dehydrogenase.
Glutamate dehydrogenase, in silico, Chloroquine, Mefloquine, NADP.
- Stillman TJ. Conformational flexibility in glutamate dehydrogenase role of water in substrate recognition and catalysis. Journal of Molecular Biology. 1993 Dec 20;234(4):1131-1139.doi: 10.1006/jmbi.1993.1665.
- Spanaki C, Plaitakis A. The role of glutamate dehydrogenase in mammalian ammonia metabolism. Neurotoxicity Research. 2012 Jan 1;21:117-127.doi: 10.1007/s12640-011-9285-4.
- Deponte M. Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochimica et Biophysica Acta. 2013 May 1;1830(5):3217-3266.doi: 10.1016/j.bbagen.2012.09.018.
- Meister A. Glutathione metabolism and its selective modification. Journal of Biological Chemistry. 1988 Nov 25;263(33):17205-17208.
- Masutani H, Yodoi J. Protein Sensors and Reactive Oxygen Species- Part A: Selenoproteins and Thiredoxin. In Methods in Enzymology, Academic Press. 2002 Mar 1;347:pp. 279-286.
- Valette O et al. Biochemical function, molecular structure and evolution of an atypical thioredoxin reductase from desulfovibrio vulgaris. Frontiers in Microbiology. 2017 Sept 29.doi: 10.3389/fmicb.2017.01855.
- Lee S, Kim SM, Lee RT. Thioredoxin and thioredoxin target proteins: From molecular mechanisms to functional significance. Antioxidants and Redox Signaling. 2013 Apr 1;18(10):1165-1207.doi: 10.1089/ars.2011.4322.
- Aparicio IM et al. Susceptibility of Plasmodium falciparum to glutamate dehydrogenase inhibitors-a possible new antimalarial target. Molecular and Biochemical Parasitology. 2010 Aug 1;172(2):152-155.doi: 10.1016/j.molbiopara.2010.04.002.
- Zocher K, Fritz-Wolf K, Kehr S. Biochemical and structural characterization of Plasmodium falciparum glutamate dehydrogenase 2. Molecular and Biochemical Parasitology. 2012 May 1;183(1):52-62.doi: 10.1016/j.molbiopara.2012.01.007.
- Beale JM. and Block JH. Antimalarials. In Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, Edited by Block JH. Lippincott Williams and Wilkins, New Delhi. 2011; 12th ed: pp. 242-257.
- Foye WO, Lemke TL and Williams DA. Antiparasitic agents. In Foye’s Principles of Medicinal Chemistry, Edited by Lemke TL. Lippincott Williams and Wilkins, New Delhi. 2007; 5th ed: pp. 867-890.
- Klingenstein R, Melnyk P. Similar structure-activity relationships of quinoline derivatives for antiprion and antimalarial effects. Journal of Medicinal Chemistry. 2006 Aug 1;49(17):5300-5308.doi: 10.1021/jm0602763.
- Singh K et al. Quinoline-Pyrimidine hybrids: Synthesis, antiplasmodial activity, SAR and mode of action studies. Journal of Medicinal Chemistry. 2014 Dec 19;57(2):435-448.doi: 10.1021/jm4014778
- Bawa S et al. Structural modifications of quinoline-based antimalarial agents: Recent developments. Journal of Pharmacy & Bioallied Sciences. 2010 Jun 1;2(2):64-71.doi: 10.4103/0975-7406.67002.
- Werner C et al. The crystal structure of plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs. Journal of Molecular Biology. 2005 Jun 10 ;349(3):597-607.doi: 10.1016/j.jmb.2005.03.077.
- Badeliya SN, Sen DJ. Bioreceptor Platform: A Macromolecular Bed for Drug Design. Asian Journal of Research in Chemistry. 2010 Dec 1;3(4):812-20.
- Zahid Hosen SM et al. Drug Bank: An Update-Resource for in Silico Drug Discovery. Research Journal of Pharmaceutical Dosage Forms and Technology. 2012 Jun 1;4(3):166-171.
- Thomas R et al. In silico Docking Approach of Coumarin Derivatives as an Aromatase Antagonist. Research Journal of Pharmacy and Technology. 2015 Dec 1;8(12):1673-1678.doi: 10.5958/0974-360X.2015.00302.9.
- Kapruwan K, Parida R, Muniyan R. In silico mutational study reveal improved interaction between Beta-Hexosaminidase A and GM2 activator essential for the breakdown of GM2 and GA2 Gangliosides on Tay-Sachs disease. Research Journal of Pharmacy and Technology. 2017 Sept 20;10(11):3899-3902.doi: 10.5958/0974-360X.2017.00708.9.
- Zadorozhnii PV et al. In Silico Prediction and Molecular Docking Studies of N-Amidoalkylated Derivatives of 1,3,4-Oxadiazole as COX-1 and COX-2 Potential Inhibitors. Research Journal of Pharmacy and Technology. 2017;10(11):3957-3963.doi: 10.5958/0974-360X.2017.00718.1.
- Kamath V, Pai A, Raj R. In Silico approach for the Rational Design of Tankyrase I Inhibitors–A Case Study on Flavone based Anticancer Leads. Research Journal of Pharmacy and Technology. 2018; 11(10): 4511-4514.doi: 10.5958/0974-360X.2018.00825.9.
- Singh A, Singh S, Anbarasu A. In silico Evaluation of Non-Synonymous SNPs in IRS-1 Gene associated with type II Diabetes Mellitus. Research Journal of Pharmacy and Technology. 2018;11(5):1957-1961.doi: 10.5958/0974-360X.2018.00363.3.
- Sensharma P, Anbarasu K, Jayanthi S. In silico Identification of Novel Inhibitors against Plasmodium falciparum Triosephosphate Isomerase from Anti-Folate Agents. Research Journal of Pharmacy and Technology. 2018;11(8):3367-3370.doi: 10.5958/0974-360X.2018.00619.4.
- Rathi S, Patel D, Shah S. Physicochemical Characterization and In-vitro Dissolution Behavior of Artemether and Lumefantrine: Hydroxypropyl-Β-Cyclodextrin Inclusion Complex. Research Journal of Pharmacy and Technology. 2020;13(3):1137-1141.doi: 10.5958/0974-360X.2020.00209.7.
- Panchal II et al. In silico Analysis and Molecular Docking Studies of Novel 4-Amino-3-(isoquinolin-4-yl)-1-H-pyrazolo[3,4-d]pyrimidine Derivatives as Dual PI3-K/mTOR Inhibitors. Current Drug Discovery Technologies. 2019;16(3):297-306.doi: 10.2174/1568009618666181102144934.
- Badeliya SN et al. In silico analysis, synthesis and biological evaluation of triazole derivatives as a H1 receptor antagonist. Current Drug Discovery Technologies. 2020 Jun 2.18(4):492-502.doi: 10.2174/1568009620666200421082221.
Abstract Views: 9
PDF Views: 0