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International Journal of Genetic Modifications and Recombinations Original Research

Exploring Azadirachta indica’s Potential to Combat Visceral Leishmaniasis Through GP63 Inhibition

  1. Mohammed Abrar Department of Bioinformatics, BioNome, Bengaluru

Abstract

Objectives: Millions of people worldwide suffer from the parasite disease visceral leishmaniasis. Determine the naturally occurring active ingredients in Azadirachta indica, which are employed as a disease-prevention agent and have several uses in medicine. To choose the best ligand to use as a medication, absorption, distribution, metabolism, and excretion (ADME) studies and molecular docking are employed.

Methods: To obtain the GP63 protein, the Protein Data Bank (PDB) database was accessed. The IMPPAT database was utilised to obtain phytocompounds. The pharmacokinetic characteristics of these drugs were evaluated using in silico ADME analysis. PyRx is used for molecular docking.

Results: Molecular docking analysis revealed promising interactions between the selected Azadirachta indica phytocompound and the GP63 protein, indicating its potential as inhibitor of Leishmania parasite virulence. 6-Deacetylnimbin demonstrated significant binding affinity with GP63, warranting further investigation. Furthermore, the phytocompound exhibited favourable pharmacokinetic properties, suggesting their suitability for drug development.

Conclusion: The phytocompound 6-Deacetylnimbin exhibits a promising binding affinity with the GP63 protein, making it a potential therapeutic candidate for the treatment of visceral leishmaniasis.

Keywords

References (34)

  1. Mathison BA, Bradley BT. Review of the Clinical Presentation, Pathology, Diagnosis, and Treatment of Leishmaniasis. Laboratory Medicine. 2022;54(4):363-371. doi:10.1093/labmed/lmac134
  2. Reimão JQ, Coser EM, Lee MR, Coelho AC. Laboratory Diagnosis of Cutaneous and Visceral Leishmaniasis: Current and Future Methods. Microorganisms. 2020;8(11):1632. doi:10.3390/microorganisms8111632
  3. Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. The Lancet Infectious Diseases. 2007;7(9):581-596. doi:10.1016/s1473-3099(07)70209-8
  4. Amato VS, Tuon FF, Bacha HA, Neto VA, Nicodemo AC. Mucosal leishmaniasis. Acta Tropica. 2008;105(1):1-9. doi:10.1016/j.actatropica.2007.08.003
  5. Costa CHN, Chang KP, Costa DL, Cunha FVM. From Infection to Death: An Overview of the Pathogenesis of Visceral Leishmaniasis. Pathogens. 2023;12(7):969. doi:10.3390/pathogens12070969
  6. Chauhan P, Shukla D, Chattopadhyay D, Saha B. Redundant and regulatory roles for Toll-like receptors inLeishmaniainfection. Clinical and Experimental Immunology. 2017;190(2):167-186. doi:10.1111/cei.13014
  7. Nylén S, Sacks D. Interleukin-10 and the pathogenesis of human visceral leishmaniasis. Trends in Immunology. 2007;28(9):378-384. doi:10.1016/j.it.2007.07.004
  8. Freitas-Junior LH, Chatelain E, Kim HA, Siqueira-Neto JL. Visceral leishmaniasis treatment: What do we have, what do we need and how to deliver it? International Journal for Parasitology: Drugs and Drug Resistance. 2012;2:11-19. doi:10.1016/j.ijpddr.2012.01.003
  9. Mazire P, Agarwal V, Roy A. Road‐map of pre‐clinical treatment for Visceral Leishmaniasis. Drug Development Research. 2021;83(2):317-327. doi:10.1002/ddr.21907
  10. Bharat P, Sagar R, Sulav R, Ankit P. Investigations of antioxidant and antibacterial activity of leaf extracts of Azadirachta indica. African Journal of Biotechnology. 2015;14(46):3159-3163. doi:10.5897/ajb2015.14811
  11. Parvez MK, Tabish Rehman M, Alam P, Al-Dosari MS, Alqasoumi SI, Alajmi MF. Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: Cell culture and molecular docking study. Saudi Pharmaceutical Journal. 2019;27(3):389-400. doi:10.1016/j.jsps.2018.12.008
  12. Olwenyi OA, Asingura B, Naluyima P, Anywar GU, Nalunga J, Nakabuye M, et al. In-vitro Immunomodulatory activity of Azadirachta indica A.Juss. Ethanol: water mixture against HIV associated chronic CD4+ T-cell activation/ exhaustion. BMC Complementary Medicine and Therapies. 2021;21(1). doi:10.1186/s12906-021-03288-0
  13. Faccin-Galhardi LC, Ray S, Lopes N, Ali I, Espada SF, dos Santos JP, et al. Assessment of antiherpetic activity of nonsulfated and sulfated polysaccharides from Azadirachta indica. International Journal of Biological Macromolecules. 2019;137:54-61. doi:10.1016/j.ijbiomac.2019.06.129
  14. Tiwari V, Darmani NA, Yue BYJT, Shukla D. In vitro antiviral activity of neem (Azardirachta indica L.) bark extract against herpes simplex virus type‐1 infection. Phytotherapy Research. 2010;24(8):1132-1140. doi:10.1002/ptr.3085
  15. Chagas ACS, Vieira LS, Freitas AR, Araújo MRA, Araújo-Filho JA, Araguão WR, et al. Anthelmintic efficacy of neem (Azadirachta indica A. Juss) and the homeopathic product Fator Vermes® in Morada Nova sheep. Veterinary Parasitology. 2008;151(1):68-73. doi:10.1016/j.vetpar.2007.10.003
  16. Dayakar A, Chandrasekaran S, Veronica J, Sundar S, Maurya R. In vitro and in vivo evaluation of anti-leishmanial and immunomodulatory activity of Neem leaf extract in Leishmania donovani infection. Experimental Parasitology. 2015;153:45-54. doi:10.1016/j.exppara.2015.02.011
  17. Shrefller WG, Burns JM, Badaró R, Ghalib HW, Button LL, McMaster WR, et al. Antibody Responses of Visceral Leishmaniasis Patients to gp63, a Major Surface Glycoprotein ofLeishmaniaSpecies. Journal of Infectious Diseases. 1993;167(2):426-430. doi:10.1093/infdis/167.2.426
  18. Laskowski RA, Jabłońska J, Pravda L, Vařeková RS, Thornton JM. PDBsum: Structural summaries of PDB entries. Protein Science. 2017;27(1):129-134. doi:10.1002/pro.3289
  19. Mohanraj K, Karthikeyan BS, Vivek-Ananth RP, Chand RPB, Aparna SR, Mangalapandi P, et al. IMPPAT: A curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics. Scientific Reports. 2018;8(1). doi:10.1038/s41598-018-22631-z
  20. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017;7(1). doi:10.1038/srep42717
  21. Nendza M, Müller M. Screening for low aquatic bioaccumulation (1): Lipinski's ‘Rule of 5’ and molecular size. SAR and QSAR in Environmental Research. 2010;21(5-6):495-512. doi:10.1080/1062936x.2010.502295
  22. Ready P. Epidemiology of visceral leishmaniasis. Clinical Epidemiology. 2014:147. doi:10.2147/clep.s44267
  23. Chen X, Li H, Tian L, Li Q, Luo J, Zhang Y. Analysis of the Physicochemical Properties of Acaricides Based on Lipinski's Rule of Five. Journal of Computational Biology. 2020;27(9):1397-1406. doi:10.1089/cmb.2019.0323
  24. Sharma S, Sharma A, Gupta U. Molecular Docking Studies on the Anti-Fungal Activity of Allium Sativum (Garlic) Against Mucormycosis (Black Fungus) by BIOVIA Discovery Studio Visualizer 21.1.0.0. 2021. doi:10.21203/rs.3.rs-888192/v1
  25. M. A, O. A. O, A. R. K. Antibacterial Activities of Azadirachta Indica against Some Bacterial Pathogens. Advances in Life Sciences. 2012;2(2):5-8. doi:10.5923/j.als.20120202.02
  26. Muhammad S, Fatima N. In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides. Pharmacognosy Magazine. 2015;11(42):123. doi:10.4103/0973-1296.157712
  27. Alves F, Bilbe G, Blesson S, Goyal V, Monnerat S, Mowbray C, et al. Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives. Clinical Microbiology Reviews. 2018;31(4). doi:10.1128/cmr.00048-18
  28. Kumar R, Bhatia M, Pai K. Role of Cytokines in the Pathogenesis of Visceral Leishmaniasis. Clinical Laboratory. 2017;63(10/2017). doi:10.7754/clin.lab.2017.170404
  29. Loganathan T, Barathinivas A, Soorya C, Balamurugan S, Nagajothi TG, Ramya S, et al. Physicochemical, Druggable, ADMET Pharmacoinformatics and Therapeutic Potentials of Azadirachtin - a Prenol Lipid (Triterpenoid) from Seed Oil Extracts of Azadirachta indica A. Juss. Journal of Drug Delivery and Therapeutics. 2021;11(5):33-46. doi:10.22270/jddt.v11i5.4981
  30. Tiwari N, Kumar A, Singh AK, Bajpai S, Agrahari AK, Kishore D, et al. Leishmaniasis control: limitations of current drugs and prospects of natural products. In: Discovery and Development of Therapeutics from Natural Products Against Neglected Tropical Diseases. Elsevier; 2019. pp. 293–350.
  31. Wijnant GJ, Dumetz F, Dirkx L, Bulté D, Cuypers B, Van Bocxlaer K, et al. Tackling drug resistance and other causes of treatment failure in leishmaniasis. Frontiers in Tropical Diseases. 2022;3:837460.
  32. Tiwari N, Gedda MR, Tiwari VK, Singh SP, Singh RK. Limitations of Current Therapeutic Options, Possible Drug Targets and Scope of Natural Products in Control of Leishmaniasis. Mini-Reviews in Medicinal Chemistry. 2017;18(1). doi:10.2174/1389557517666170425105129
  33. Faccin-Galhardi LC, Aimi Yamamoto K, Ray S, Ray B, Carvalho Linhares RE, Nozawa C. The in vitro antiviral property of Azadirachta indica polysaccharides for poliovirus. Journal of Ethnopharmacology. 2012;142(1):86-90. doi:10.1016/j.jep.2012.04.018
  34. Pramanik A, Paik D, Pramanik PK, Chakraborti T. Serine protease inhibitors rich Coccinia grandis (L.) Voigt leaf extract induces protective immune responses in murine visceral leishmaniasis. Biomed Pharmacother. 2019;111:224–235. doi: 10.1016/ j.biopha.2018. 12.053.