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Research and Reviews: A Journal of Pharmaceutical Science Review Article

Targeting Dystrophin Restoration and Neuroprotection in Duchenne Muscular Dystrophy: Insights from Withania somnifera

  1. Siddhartha Pandurangi Department of Biotechnology, M.S. Ramaiah University of Applied Sciences, Bengaluru

Abstract

Duchenne muscular dystrophy is a genetic disorder. This disease affects men more common than women. Main objective of the present study was to identify the naturally active phytocompounds from Withania somnifera (Ashwagandha). Ashwagandha has a great value in the field of Ayurveda and Indian medicine and is used for treating muscular and neurological disorders. Toxicity prediction, molecular docking, statistical information, drug illness prediction, and Absorption, distribution, metabolism, excretion, and toxicity analysis were used to predict the phytocompounds as a drug. Protein Data bank database was used to retrieve the Dystrophin protein and its chains. The poor binding affinity of the ligands with the targeted protein was removed. Toxicity and ADME analysis were done using ADMET lab 2.0 and Swiss ADME tools, respectively and molecular docking was done using PyRx. The Ramachandran plot displays the protein's dihedral angles ψ against φ. Absorption, distribution, metabolism, excretion, and toxicity analysis and molecular docking results showed Withaferine A, Somniferine, Coagulin Q, Physagulin D, Viscosalactone B have effective binding affinity towards Dystrophin protein and possess the properties of a drug which is safe to consume. Previous and present studies suggested that Withaferine A, Somniferine, Coagulin Q, Physagulin D, and Viscosalactone B could inhibit the A, B, C, and D chains of the Human Dystrophin protein and have effective binding affinity. The therapeutic strategies against Duchenne Muscular Dystrophy are based on molecular docking and ADMET analysis. Thus, the phytocompounds of Ashwagandha can be potential drug candidates.

Keywords

References (58)

  1. Falzarano M, Scotton C, Passarelli C, Ferlini A. Duchenne Muscular Dystrophy: From Diagnosis to Therapy. Molecules. 2015;20(10):18168-18184. doi:10.3390/molecules201018168
  2. Banik DS. A CRITICAL REVIEW ON DUCHENNE MUSCULAR DYSTROPHY THROUGH AYURVEDA–A PRACTICAL APPROACH. World Journal of Pharmaceutical Research. 2017:864-872. doi:10.20959/wjpr20178-9205
  3. Elangkovan N, Dickson G. Gene Therapy for Duchenne Muscular Dystrophy. Journal of Neuromuscular Diseases. 2021;8(s2):S303-S316. doi:10.3233/jnd-210678
  4. Fortunato F, Farnè M, Ferlini A. The DMD gene and therapeutic approaches to restore dystrophin. Neuromuscular Disorders. 2021;31(10):1013-1020. doi:10.1016/j.nmd.2021.08.004
  5. Jain M. Neuro-muscular diseases, Muscular dystrophies, Parkinson’s disease, Autism, Cerebral Palsy and mentally challenged children.
  6. Davies KE, Nowak KJ. Molecular mechanisms of muscular dystrophies: old and new players. Nature Reviews Molecular Cell Biology. 2006;7(10):762-773. doi:10.1038/nrm2024
  7. Fairclough RJ, Wood MJ, Davies KE. Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nature Reviews Genetics. 2013;14(6):373-378. doi:10.1038/nrg3460
  8. Duan D. Micro-Dystrophin Gene Therapy Goes Systemic in Duchenne Muscular Dystrophy Patients. Human Gene Therapy. 2018;29(7):733-736. doi:10.1089/hum.2018.012
  9. Chaturvedi A, Rao PN, U S, Kumar MA. ROLE OF PANCHAKARMA IN DUCHENNE MUSCULAR DYSTROPHY. International Journal of Research in Ayurveda and Pharmacy. 2013;4(2):272-275. doi:10.7897/2277-4343.04238
  10. By Akhoury Gourang Sinha, Principles and Practice of Therapeutic massage Jaypeebrothers medical publishers. Edition. 243.
  11. Mukesh J. Yoga Annapurna & pandey MP preliminary study of integrated approach of panchakarma, yoga & Ayurvedic medicine in the management of muscular dystrophy. world health review. 2002; 1:1–33.
  12. Agnivesa C, Chakrapannidatta A. Charaka Samhita With Chakrapannidatta, Ayurveda Dipika. Commentary. 2008;731–2.
  13. Shailaja U, Prasanna N Rao KJ. Clinical study on efficacy of rajayapana basti & Baladi yoga in motor disabilities of CP in children. 2014;35.
  14. Bitencourt-Ferreira G, Pintro VO, de Azevedo WF Jr. Docking with AutoDock4. In: Methods in Molecular Biology. New York, NY: Springer New York; 2019. p. 125–48.
  15. 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
  16. Pollastri MP. Overview on the Rule of Five. Current Protocols in Pharmacology. 2010;49(1). doi:10.1002/0471141755.ph0912s49
  17. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1. Advanced Drug Delivery Reviews. 2001;46(1-3):3-26. doi:10.1016/s0169-409x(00)00129-0
  18. Ghose AK, Viswanadhan VN, Wendoloski JJ. A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases. Journal of Combinatorial Chemistry. 1998;1(1):55-68. doi:10.1021/cc9800071
  19. Dong J, Wang NN, Yao ZJ, Zhang L, Cheng Y, Ouyang D, et al. ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. Journal of Cheminformatics. 2018;10(1). doi:10.1186/s13321-018-0283-x
  20. Schlede E, Genschow E, Spielmann H, Stropp G, Kayser D. Oral acute toxic class method: A successful alternative to the oral LD50 test. Regulatory Toxicology and Pharmacology. 2005;42(1):15-23. doi:10.1016/j.yrtph.2004.12.006
  21. Ibraghimov-Beskrovnaya O, Ervasti JM, Leveille CJ, Slaughter CA, Sernett SW, Campbell KP. Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature. 1992;355(6362):696-702. doi:10.1038/355696a0
  22. Nigro V, Savarese M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. 2014;33(1):1–12.
  23. Buysse K, Riemersma M, Powell G, Van Reeuwijk J, Chitayat D, Roscioli T, et al. Missense mutations in beta-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome. Hum Mol Genet. 2013; 22:1746–54.
  24. Carss KJ, Stevens E, Foley AR, Cirak S, Riemersma M, Torelli S, et al. Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of alpha-dystroglycan. Am J Hum Genet. 2013; 93:29–41.
  25. Di Costanzo S, Balasubramanian A, Pond HL, Rozkalne A, Pantaleoni C, Saredi S, et al. POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations. Human Molecular Genetics. 2014;23(21):5781-5792. doi:10.1093/hmg/ddu296
  26. Longman C. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of -dystroglycan. Human Molecular Genetics. 2003;12(21):2853-2861. doi:10.1093/hmg/ddg307
  27. Ogawa M, Nakamura N, Nakayama Y, Kurosaka A, Manya H, Kanagawa M, et al. GTDC2 modifies O-mannosylated alpha-dystroglycan in the endoplasmic reticulum to generate N-acetyl glucosamine epitopes reactive with CTD110.6 antibody. Biochem Biophys Res Commun. 2013; 440:88–93.
  28. Willer T, Lee H, Lommel M, Yoshida-Moriguchi T, de Bernabe DBV, Venzke D, et al. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nature Genetics. 2012;44(5):575-580. doi:10.1038/ng.2252
  29. Gomaa MS, Ali IAI, El Enany G, El Ashry ESH, El Rayes SM, Fathalla W, et al. Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition. Molecules. 2022;27(23):8279. doi:10.3390/molecules27238279
  30. Korenbaum E, Rivero F. Calponin homology domains at a glance. Journal of Cell Science. 2002;115(18):3543-3545. doi:10.1242/jcs.00003
  31. Broderick MJF, Winder SJ. Spectrin, α-Actinin, and Dystrophin. Advances in Protein Chemistry. 2005:203-246. doi:10.1016/s0065-3233(05)70007-3
  32. Koenig M, Monaco AP, Kunkel LM. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell. 1988;53(2):219-228. doi:10.1016/0092-8674(88)90383-2
  33. Amann KJ, Renley BA, Ervasti JM. A Cluster of Basic Repeats in the Dystrophin Rod Domain Binds F-actin through an Electrostatic Interaction. Journal of Biological Chemistry. 1998;273(43):28419-28423. doi:10.1074/jbc.273.43.28419
  34. Rumeur L, Fichou E, Pottier Y, Gaboriau S, Rondeau-Mouro F, Vincent C, et al. Interaction of dystrophin rod domain with membrane phospholipids. Evidence of a close proximity between tryptophan residues and lipids. J Biol Chem. 2003; 278:5993–6001.
  35. Koenig M, Kunkel LM. Detailed analysis of the repeat domain of dystrophin reveals four potential hinge segments that may confer flexibility. Journal of Biological Chemistry. 1990;265(8):4560-4566. doi:10.1016/s0021-9258(19)39599-7
  36. Ilsley JL, Sudol M, Winder SJ. The WW domain: Linking cell signalling to the membrane cytoskeleton. Cellular Signalling. 2002;14(3):183-189. doi:10.1016/s0898-6568(01)00236-4
  37. Rentschler S, Linn H, Deininger K, Bedford MT, Espanel X, Sudol M. The WW Domain of Dystrophin Requires EF-Hands Region to Interact with β-Dystroglycan. Biological Chemistry. 1999;380(4). doi:10.1515/bc.1999.057
  38. Ponting CP, Blake DJ, Davies KE, Kendrick-Jones J, Winder SJ. ZZ and TAZ: new putative zinc fingers in dystrophin and other proteins. Trends in Biochemical Sciences. 1996;21(1):11-13. doi:10.1016/s0968-0004(06)80020-4
  39. Anderson JT, Rogers RP, Jarrett HW. Ca2⁺-Calmodulin Binds to the Carboxyl-terminal Domain of Dystrophin. Journal of Biological Chemistry. 1996;271(12):6605-6610. doi:10.1074/jbc.271.12.6605
  40. Ayalon G, Davis JQ, Scotland PB, Bennett V. An Ankyrin-Based Mechanism for Functional Organization of Dystrophin and Dystroglycan. Cell. 2008;135(7):1189-1200. doi:10.1016/j.cell.2008.10.018
  41. Bhosle RC, Michele DE, Campbell KP, Li Z, Robson RM. Interactions of intermediate filament protein synemin with dystrophin and utrophin. Biochemical and Biophysical Research Communications. 2006;346(3):768-777. doi:10.1016/j.bbrc.2006.05.192
  42. BLAKE D, TINSLEY J, DAVIES K, KNIGHT A, WINDER S, KENDRICKJONES J. Coiled-coil regions in the carboxy-terminal domains of dystrophin and related proteins: potentials for protein-protein interactions. Trends in Biochemical Sciences. 1995;20(4):133-135. doi:10.1016/s0968-0004(00)88986-0
  43. Sadoulet-Puccio HM, Rajala M, Kunkel LM. Dystrobrevin and dystrophin: An interaction through coiled-coil motifs. Proceedings of the National Academy of Sciences. 1997;94(23):12413-12418. doi:10.1073/pnas.94.23.12413
  44. Dar NJ, Ahmad M. Neurodegenerative diseases and Withania somnifera (L.): An update. Journal of Ethnopharmacology. 2020;256:112769. doi:10.1016/j.jep.2020.112769
  45. Rastogi RP, Mehrotra BN. Compendium of Indian medicinal plants, 2nd Reprint, Central Drug Research Institute, Lucknow and National Institute of Science Communication, Council of Scientific and Industrial Research. New Delhi; 1998.
  46. Bhattacharya A, Ghosal S, Bhattacharya SK. Antioxidant effect of Withania somnifera glycowithanolides in chronic footshock stress-induced perturbations of oxidative free radical scavenging enzymes and lipid peroxidation in rat frontal cortex and striatum. J Ethnopharmacol. 2001; 74:1–6.
  47. Nadkarni KM. Indian materia medica, (Popular Prakshan Limited: Bombay). 1291.
  48. Lohar DR, Chaturvedi D, Varma PN. Mineral elements of a few medicinally important plants, Ind. Ind Drugs. 1992;29:271–3.
  49. Mohanty I, Arya DS, Dinda A, Talwar KK, Joshi S, Gupta SK. Mechanisms of Cardioprotective effect of Withania somnifera in experimentally induced myocardial infarction, Basic clin. Basic clin Pharmacol Toxicol. 2004;94(4):184–90.
  50. Bilal Ahmad Mi J, Nisar A. Tanvir-ul Hasan, Sushma Koul, Botanical, chemical and pharmacological review of Withania somnifera (Indian ginseng): an ayurvedic medicinal plant. Indian Journal of Drugs and Diseases. 2012;1(6):147–60.
  51. Andulla B, Radhika B. Hypoglycemic, diuretic and hypocholesterolemic effect of winter cherry (Withania somnifera) root. Indian J Exp Biol. 2000; 38:607–9.
  52. Battacharya SK. Adaptogenic activity of Withania somnifera an experimental study using a rat model of chronic stress. Journal of Pharmacological. 2003;75(3):547–55575.
  53. Rani A, Baranwal NR, Nema RK. Pharmacognostical & Phytochemical studies of Withania somnifera. Asian Journal of Biochemical and Pharmaceutical Research. 2012;2(4):195–8.
  54. Qamar U, Samiulla L, Singh VK, Jamil S. Phytochemical and Pharmacological Profile of Withania somnifera Dunal: A Review. Journal of Applied Pharmaceutical Science. 2012;2(1):170–5.
  55. Devi PU, Sharada AC, Solomon FE. Antitumor and radiosensitizing effects of Withania somnifera (ashwagandha) on a transplantable mouse tumor, Sarcoma-180, Ind. J Exp Biol. 1993;31:607–11.
  56. Davis L, Kuttan G. Suppressive effect of cyclophosphamide-induced toxicity by Withania somnifera extract in mice. Journal of Ethnopharmacology. 1998;62(3):209-214. doi:10.1016/s0378-8741(98)00039-7
  57. Malhotra CL, Mehta VL, Das PK, Dhalla NS. Studies on Withania-ashwagandha, Kaul. V. The effect of total alkaloids (ashwagandholine) on the central nervous system, Ind. J Physiol Pharmacol. 1965; 9:127–36.
  58. Sehgal N, Gupta A, Khader R, Shanker V, Joshi D, Mills JT, et al. Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver, Proc. Proc Nat Acad Sci. 2012;109(9):3510–5.
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