A comparative computational approach on the most deleterious missense variant in Connexin 43 protein and its potent inhibitor analysis

Katturajan, Ramkumar ; Medha, Tamma ; Karra, Sakshi ; R, Vidya ; Evan Prince, Sabina

Abstract

Intercellular communication between the cell plays an essential role in cell growth and cell formation, including migration, metabolism, and cell differentiation. Cell function and tissue homeostasis are maintained through gap junction intercellular communication (GJIC), thus regulating connexin hemichannels. Mis regulation of such connexin, especially connexin (Cx) 43, affects a comprehensive process, including cell differentiation, inflammation, and cell death. Mis regulation may be due to the missense variant in Cx43. Thus, we screened the complete set of mutations from public mutational databases and obtained 219 missense variants, which were then classified based on their pathogenicity, functional impact, stability, conservation, and physiochemical properties. Variant L214P was scrutinized to have the most deleterious, which was then modelled using the I-TASSER server and performed molecular docking analysis to screen potent inhibitors. The compound Kanamycin, Ginsenoside, and Astragaloside IV have better interactions with Cx43 mutant with a maximum of 5 hydrogen bonds. Ginsenoside is a compound that follows a Lipinski rule of five. Thus, the result obtained from this study suggests that Ginsenoside would be a better potent inhibitor for native and mutant Cx43.

Keyword(s)

Cx43; L214P; Virtual screening; Variant classification; Molecular docking

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