Targeting OPA1 protein for therapeutic intervention in autosomal dominant optic atrophy: In silico drug discovery

Abstract

Autosomal dominant hereditary optic atrophy (ADOA) is a prevalent hereditary condition characterized by the gradual and simultaneous deterioration of vision. Mutations in Optic atrophy 1 (OPA1) have been linked to ADOA, the prevailing form of inherited optic neuropathy. However, the current therapeutic options are limited. This study aimed to identify a drug-like molecule that can serve as an activator of the OPA1 GTPase domain, using in silico virtual screening and molecular dynamic simulation pipeline. A ligand-based pharmacophore model was generated to identify the important biological entities in natural compounds, followed by virtual screening pipeline. Total 55,96,00 drug-like compounds were screened and then subsequently proceed for molecular docking, molecular dynamics simulation (200ns), MM-PBSA analysis, and ADMET (Swiss ADME server) studies. Virtual screening revealed the top-ranked compound ZINC000009190697 (−8 kcal/mol). Furthermore, the stability of the top hit compound at the active site of OPA1 was demonstrated using molecular dynamics simulations and MM-PBSA calculations. ADMET analysis assisted in the identification of the top hit compound as possible activators of OPA1 with optimal drug-like properties. These results indicated that there is need of further experimental assessment of the top-hit compound ZINC000009190697 in wet lab to confirm its efficacy as a potential OPA1 activator in both in vitro and in vivo studies.