Pharmacophore based drug designing of COL7A1; The causative gene of Dystrophic Epidermolysis Bullosa

Abstract

Epidermolysis Bullosa is a rare genetic disorder that causes skin fragility, trauma induced dissociations 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 a different subtype of EB. Dystrophic Epidermolysis Bullosa (DEB) is one of the subtypes 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 DEB in the market yet. So, it is the need of the hour to come up with a potential inhibitor that could inhibit the faulty protein of COL7A1 gene. Different exons of COL7A1 have been analyzed and exon no 70 to 75 has been selected which were important for mutational point of view. The mutations in it have been identified and verified using various In-silico tools. The 3D structure of the protein has been retrieved using specific exons which were edited and mutations were introduced in it and it was further checked to analyze its stability, toxicity and solubility of the protein. The inhibitors of COL7A1 have been formed using CAAD techniques (pharmacophore modeling) and the best inhibitor of COL7A1 has been further checked to determine its drug-likeness, solubility, its toxicity, and various physiochemical properties. The constructed inhibitor was found to have the best docking results and found to have good ADMET properties. The developed inhibitor construct showing promising results In-silico and it will also 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.

Genetic diagnosis of a rare COL7A1 variant causing dystrophic epidermolysis bullosa pruriginosa through whole‑exome sequencing

“…Using I-TASSER, the finest structure prediction tool, the molecular basis of the influence of variants on functional changes was analyzed. The collagen molecule requires a glycine residue to maintain its specific triple helical conformation ( 45 , 46 ). In the present cases, arginine residues were substituted for a glycine residue.…”

Phytochemical Profiling, Biological Activities and In Silico Virtual Screening of Bioactive Compounds of Trichodesma Indicum (L) R. Br. Extracts

“…)‐ and stigmasterol showed the best energy binding affinity against both targets. Computational technology is widely used nowadays to discover new therapeutic compounds, including medications to treat snake bites and neurotransmitter blockers [36,37] . A potential area in drug discovery for discovering new therapeutic uses for medications that have already been researched is drug profiling [38] .…”

“…Computational technology is widely used nowadays to discover new therapeutic compounds, including medications to treat snake bites and neurotransmitter blockers. [36,37] A potential area in drug discovery for discovering new therapeutic uses for medications that have already been researched is drug profiling. [38] It provides an excellent opportunity for traditional de novo drug discovery because new molecular entities' success rate is just 2.1 % of the time, and the number of authorized pharmaceuticals has been decreasing since the 1990s.…”