In Silico Docking, ADMET and QSAR Study of few Antimalarial Phytoconstituents as Inhibitors of Plasmepsin II of P. falciparum Against Malaria

Author(s): Syeda Sabiha Salam*, Pankaj Chetia, Devid Kardong

Journal Name: Current Drug Therapy

Volume 15 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Malaria is endemic in various parts of India particularly in the North- Eastern states with Plasmodium falciparum-the most prevalent human malaria parasite. Plantderived compounds have always received tremendous importance in the area of drug discovery and development and scientific study of traditional medicinal plants are of great importance to mankind.

Objective: The present work deals with the computational study of some antimalarial compounds obtained from a few medicinal plants used by the tribal inhabitants of the North-Eastern region of India for treating malaria.

Methods: In silico methodologies were performed to study the ligand-receptor interactions. Target was identified based on the pharmacophore mapping approach. A total of 18 plant-derived compounds were investigated in order to estimate the binding energies of the compounds with their drug target through molecular docking using Autodock 4.2. ADMET filtering for determining the pharmacokinetic properties of the compounds was done using Mobyle@RPBS server. Subsequent Quantitative-Structure Activity Relationship analysis for bioactivity prediction (IC50) of the compounds was done using Easy QSAR 1.0.

Results: The docking result identified Salannin to be the most potent Plasmepsin II inhibitor while the QSAR analysis identified Lupeol to have the least IC50 value. Most of the compounds have passed the ADME/Tox filtration.

Conclusion: Salannin and Lupeol were found to be the most potent antimalarial compounds that can act as successful inhibitors against Plasmepsin II of P. falciparum. The compounds Salannin and Lupeol are found in Azadirachta indica and Swertia chirata plants respectively, abundantly available in the North-Eastern region of India and used by many inhabiting tribes for the treatment of malaria and its symptoms.

Keywords: In silico, pharmacophore-mapping approach, plasmepsin II, pharmacokinetic, inhibitors, antimalarial.

[1]
Dev V, Bhattacharyya PC, Talukdar R. Transmission of malaria and its control in the northeastern region of India. J Assoc Physicians India 2003; 51: 1073-6.
[PMID: 15260392]
[2]
Mohapatra PK, Prakash A, Bhattacharya DR, et al. Malaria situation in Northeastern region of India. Icmr Bull 1998; 28: 21-30.
[3]
Upadhyayula SM, Mutheneni SR, Chenna S, Parasaram V, Kadiri MR. Climate drivers on malaria transmission in Arunachal Pradesh, India. PLoS One 2015; 10(3)e0119514
[http://dx.doi.org/10.1371/journal.pone.0119514] [PMID: 25803481]
[4]
Van Tyne D, Dieye B, Valim C, et al. Changes in drug sensitivity and anti-malarial drug resistance mutations over time among Plasmodium falciparum parasites in Senegal. Malar J 2013; 12: 441.
[http://dx.doi.org/10.1186/1475-2875-12-441] [PMID: 24314037]
[5]
Sinha S, Medhi B, Sehgal R. Challenges of drug-resistant malaria. Parasite 2014; 21: 61.
[http://dx.doi.org/10.1051/parasite/2014059] [PMID: 25402734]
[6]
Eyasu M. Antimalarial Drug Resistance: In the Past, Current status and Future Perspectives. Br J Pharmacol 2015; 6(1): 1-15.
[PMID: 25671228]
[7]
Hill AVS. Vaccine against malaria. Philos Trans R Soc Lond B Biol Sci 2011; 366(1579): 2806-14.
[http://dx.doi.org/10.1098/rstb.2011.0091]]
[9]
Newman DJ. Natural products as leads to potential drugs: an old process or the new hope for drug discovery? J Med Chem 2008; 51(9): 2589-99.
[http://dx.doi.org/10.1021/jm0704090] [PMID: 18393402]
[10]
Paul S, Devi N, Sarma GC. Ethnobotanical utilization of some medicinal plants by Bodo people of Manas Biosphere Reserve in the treatment of malaria. Int Res J Pharmacy 2013; 4(6): 102-5.
[http://dx.doi.org/10.7897/2230-8407.04622]
[11]
Shankar R, Deb S, Sharma BK. Antimalarial plants of northeast India: An overview. J Ayurveda Integr Med 2012; 3(1): 10-6.
[http://dx.doi.org/10.4103/0975-9476.93940] [PMID: 22529674]
[12]
Wright CW. Traditional antimalarials and the development of novel antimalarial drugs. J Ethnopharmacol 2005; 100(1-2): 67-71.
[http://dx.doi.org/10.1016/j.jep.2005.05.012] [PMID: 16023812]
[13]
Ginsburg H, Deharo E. A call for using natural compounds in the development of new antimalarial treatments - an introduction. Malar J 2011; 10(Suppl. 1): S1.
[http://dx.doi.org/10.1186/1475-2875-10-S1-S1] [PMID: 21411010]
[14]
Singla RK. Editorial: in silico drug design and medicinal chemistry). Curr Top Med Chem 2015; 15(11): 971-2.
[http://dx.doi.org/10.2174/156802661511150408110453] [PMID: 25860175]
[15]
Kashyap M, Sohpal VK, Mahajan P. In silico approaches for inhibitor designing against Plasmepsin II of malaria parasite, Plasmodium malariae. Biosci Biotech Res Comm 2016; 9(1): 25-31.
[http://dx.doi.org/10.21786/bbrc/19.1/5]
[16]
Yadav DK, Kumar S, Saloni, et al. Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer. Drug Des Devel Ther 2017; 11: 1859-70.
[http://dx.doi.org/10.2147/DDDT.S130601] [PMID: 28694686]
[17]
Yadav DK, Rai R, Kumar N, et al. New arylated benzo[h]quinolines induce anti-cancer activity by oxidative stress-mediated DNA damage. Sci Rep 2016; 6: 38128.
[http://dx.doi.org/10.1038/srep38128] [PMID: 27922047]
[18]
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform 2011; 3: 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[19]
Laskowski RA, Swindells MB. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 2011; 51(10): 2778-86.
[http://dx.doi.org/10.1021/ci200227u] [PMID: 21919503]
[20]
Gleeson MP. Generation of a set of simple, interpretable ADMET rules of thumb. J Med Chem 2008; 51(4): 817-34.
[http://dx.doi.org/10.1021/jm701122q] [PMID: 18232648]
[21]
Lagorce D, Sperandio O, Baell JB, Miteva MA, Villoutreix BO. FAF-Drugs3: a web server for compound property calculation and chemical library design. Nucleic Acids Res 2015; 43(W1)W200-7
[PMID: 25883137] [http://dx.doi.org/10.1093/nar/gkv353]]
[22]
Froimowitz M. HyperChem: a software package for computational chemistry and molecular modeling. Biotechniques 1993; 14(6): 1010-3.
[PMID: 8333944]
[23]
Jaudzems K, Tars K, Maurops G, et al. Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit. ACS Med Chem Lett 2014; 5(4): 373-7.
[http://dx.doi.org/10.1021/ml4004952] [PMID: 24900843]
[25]
McKay PB, Peters MB, Carta G, et al. Identification of plasmepsin inhibitors as selective anti-malarial agents using ligand based drug design. Bioorg Med Chem Lett 2011; 21(11): 3335-41.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.015] [PMID: 21531557]
[26]
Saify ZS, Azim MK, Ahmad W, et al. New benzimidazole derivatives as antiplasmodial agents and plasmepsin inhibitors: synthesis and analysis of structure-activity relationships. Bioorg Med Chem Lett 2012; 22(2): 1282-6.
[http://dx.doi.org/10.1016/j.bmcl.2011.10.018] [PMID: 22204908]
[27]
Rasina D, Otikovs M, Leitans J, et al. Fragment-Based Discovery of 2-Aminoquinazolin-4(3H)-ones As Novel Class Nonpeptidomimetic Inhibitors of the Plasmepsins I, II, and IV. J Med Chem 2016; 59(1): 374-87.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01558] [PMID: 26670264]
[28]
Shi H, Liu K, Leong WW, Yao SQ. Expedient solid-phase synthesis of both symmetric and asymmetric diol libraries targeting aspartic proteases. Bioorg Med Chem Lett 2009; 19(14): 3945-8.
[http://dx.doi.org/10.1016/j.bmcl.2009.03.041] [PMID: 19328682]
[29]
Song Y, Jin H, Liu X, Zhu L, Huang J, Li H. Discovery of non-peptide inhibitors of Plasmepsin II by structure-based virtual screening. Bioorg Med Chem Lett 2013; 23(7): 2078-82.
[http://dx.doi.org/10.1016/j.bmcl.2013.01.128] [PMID: 23466235]
[30]
Kouznetsov VV, Gómez-Barrio A. Recent developments in the design and synthesis of hybrid molecules based on aminoquinoline ring and their antiplasmodial evaluation. Eur J Med Chem 2009; 44(8): 3091-113.
[http://dx.doi.org/10.1016/j.ejmech.2009.02.024] [PMID: 19361896]
[31]
Paramashivam SK, Elayaperumal K, Natarajan KB, et al. In silico pharmacokinetic and molecular docking studies of small molecules derived Indigofera aspalathoides Vahl targeting receptor tyrosine kinases. Bioinformation 2015; 11(2): 73-84.
[32]
Elipilla P. Designing molecular docking and toxicity studies of novel plasmepsin II inhibitors. Eur J Biotechnol Bioscience 2015; 3(9): 27-30.
[33]
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002; 45(12): 2615-23.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[34]
Gotwals B. Case Study: Drug Solubility. NCSSM Chemistry 2009.
[35]
Wal1 A, Srivastava RS, Wal1 P, et al. Lupeol as a magical drug Pharm Biol Eval 2015; 2(5): 142-51.


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 3
Year: 2020
Published on: 14 October, 2020
Page: [264 - 273]
Pages: 10
DOI: 10.2174/1574885514666190923112738

Article Metrics

PDF: 16
HTML: 2
EPUB: 1
PRC: 1