Pharmacophore Based Drug Designing of COL7A1; The Causative Gene of Dystrophic Epidermolysis Bullosa
Abstract
Abstract Views: 564Epidermolysis Bullosa (EB) is a rare genetic disorder that causes skin fragility, trauma induced dissociation of the skin and painful wound growth. More than 20 types of genes are involved in causing EB as it is a polygenic disease and each gene is involved in causing a different subtype of EB. Dystrophic Epidermolysis Bullosa (DEB) is a subtype of EB caused by mutations in the COL7A1 (Collagen Type VII Alpha 1 Chain) gene and it affects people from all racial backgrounds. No drug is available for the treatment of DEB in the market. So, it is the need of the hour to come up with a potential inhibitor that may inhibit the faulty protein of COL7A1 gene. Different exons of COL7A1 were analyzed and exons 70-75 were selected. These exons are important from a mutational point of view. The mutations in them were identified and verified using various In silico tools. The 3D structure of the protein was retrieved using specific exons (which were edited) and mutations were introduced in it. Moreover, the protein was further checked to analyze its stability, toxicity and solubility. The inhibitors of COL7A1 were formed using CAAD techniques (pharmacophore modeling) and the best inhibitor of COL7A1 was further checked to determine its drug-likeness, solubility, toxicity, and various physiochemical properties. The constructed inhibitor was found to have the best docking results and good ADMET properties. The developed inhibitor construct showed promising results In silico and it is also expected to show good results if it would be tested In vitro and In vivo. Thus, it would be a breakthrough to treat DEB using this inhibitor, if this inhibitor is constructed and further tested In vitro.
Keywords: Epidermolysis Bullosa (EB), COL7A1, inhibitors, pharmacophore, skin disorders
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Yao YY, Zhang Y, Xie XH, Chen L, Zhu F, Zhou M. Identification of a novel COL17A1 compound heterozygous mutation in a Chinese girl with non-herlitz junctional epidermolysis bullosa. Curr Med Sci. 2020;40(4):795-800. https://doi.org/10.1007/s11596-020-2234-9
Firing, C, Bygum A. Epidermolysis Bullosa. 2017:V07170568.
Chen F, Huang L, Li C, et al. Next‐generation sequencing through multigene panel testing for the diagnosis of hereditary epidermolysis bullosa in Chinese population. Clin Genetics. 2020;98(2):179-84. https://doi.org/10.1111/cge.13791
Yang WS, Kang S, Sung J, Kleinman HK. Thymosin β4: potential to treat epidermolysis bullosa and other severe dermal injuries. Euro J Dermatol. 2019;29(5):459-67. https://doi.org/10.1684/ejd.2019.3642
Naveed M, Tehreem S, Arshad S, Bukhari SA, Shabbir MA, Essa R, Ali N, Zaib S, Khan A, Al-Harrasi A, Khan I. Design of a novel multiple epitope-based vaccine: An immunoinformatics approach to combat SARS-CoV-2 strains. J Infect Public Health. 2021;14(7):938-946. https://doi.org/10.1016/j.jiph.2021.04.010
Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y. The I-TASSER Suite: protein structure and function prediction. Nat Method. 2015;12(1):7-8. https://doi.org/10.1038/nmeth.3213
Benson D, Lipman DJ, Ostell J. GenBank. Nucleic Acids Res. 1993;21(13):2963-2965.
Gasteiger E, Hoogland C, Gattiker A, Duvaud Se, Wilkins MR, Appel RD. Protein Identification and Analysis Tools on the ExPASy Server. In: Walker JM, ed. The Proteomics Protocols Handbook. Totowa, NJ: Humana Press; 2005:571-607. https://doi.org/10.1385/1-59259-890-0:571
Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bio Informatics. 2008;9(1):1-8. https://doi.org/10.1186/1471-2105-9-40
Ko J, Park H, Heo L, Seok C. GalaxyWEB server for protein structure prediction and refinement. Nucleic Acids Res. 2012;40(W1):294-297. https://doi.org/10.1093/nar/gks493
Wang W, Xia M, Chen J, et al. Data set for phylogenetic tree and RAMPAGE Ramachandran plot analysis of SODs in Gossypium raimondii and G. arboreum. Data Brief. 2016;9:345-348. https://doi.org/10.1016/j.dib.2016.05.025
Schneidman-Duhovny D, Dror O, Inbar Y, Nussinov R, Wolfson HJ. PharmaGist: a webserver for ligand-based pharmacophore detection. Nucleic Acids Res. 2008;36(suppl_2):W223-228. https://doi.org/10.1093/nar/gkn187
Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ. PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res. 2005 Jul 1;33(suppl_2):W363-367. https://doi.org/10.1093/nar/gki481
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7(1):1-13. https://doi.org/10.1038/srep42717
Koga H, Prost-Squarcioni C, Iwata H, Jonkman MF, Ludwig RJ, Bieber K. Epidermolysis bullosa acquisita: the 2019 update. Front Med. 2019;5(362):1-28. https://doi.org/10.3389/fmed.2018.00362
Prodinger C, Reichelt J, Bauer JW, Laimer M. Epidermolysis bullosa: advances in research and treatment. Exp Dermatol. 2019;28(10):1176-1189. https://doi.org/10.1111/exd.13979
Ludwig RJ. Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita. Int Sch Res Notices. 2013;2013:1-25. http://dx.doi.org/10.1155/2013/812029
Khan KM, Ambreen N, Taha M, et al. Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors. J Comput Aided Mol Des. 2014 May;28(5):577-585. https://doi.org/10.1007/s10822-014-9745-z
Afzal MS, Khan A, Qureshi UU, et al. Community-based assessment of knowledge, attitude, practices and risk factors regarding COVID-19 among Pakistanis residents during a recent outbreak: a cross-sectional survey. J Comm Health. 2021;46(3):476-486. https://doi.org/10.1007/s10900-020-00875-z
Zahra A, Saleem MA, Javed H, Khan MA, Naveed M, Shakoori AR. Single Nucleotide Polymorphism Induces a Positive Selection Pressure at Gag-Pol Sites in Human Immunodeficiency Virus Favoring Drug Resistance Mutations. Pak J Zool. 2021;2021:1-17. https://dx.doi.org/10.17582/journal.pjz/20200525130507
Koga H, Recke A, Vidarsson G, et al. PDE4 inhibition as potential treatment of epidermolysis bullosa acquisita. J Investig Dermatol. 2016 Nov;136(11):2211-2220. https://doi.org/10.1016/j.jid.2016.06.619
Kern JS, Loeckermann S, Fritsch A, et al. Mechanisms of fibroblast cell therapy for dystrophic epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity. Mol Therapy. 2009;17(9):1605-1615. https://doi.org/10.1038/mt.2009.144
Wong T, Gammon L, Liu L, et al. Potential of fibroblast cell therapy for recessive dystrophic epidermolysis bullosa. J Investig Dermatol. 2008;128(9):2179-2189. https://doi.org/10.1038/jid.2008.78
Van den Akker PC, Jonkman MF, Rengaw T, et al.. The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations. Human Mutation. 2011;32(10):1100-1107. https://doi.org/10.1002/humu.21551
Naveed M, Mumtaz AS, Saleem MA. Role of Pyrroloquinoline Quinone in Biocontrol Together with Induced Systemic Resistance: A Novel Resource Trialed for Rice Disease Control. Intl J Agric Biol. 2020;2020:1-10.
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