Pharmacophore Modeling, Virtual Screening, Molecular Docking, DFT, and ADMET Analyses to Develop Newer generation Dual Orexin Receptor Antagonist Targeting Insomnia

Dual orexin receptor antagonists such as suvorexant, lemborexant, and daridorexant are the effective solutions for treating insomnia without inducing any dependency. In this study, we identified newer generation dual orexin receptor antagonist using receptor based pharmcophore modeling, virtual screening, molecular docking, MEP, FMO, and ADMET analyses. Two receptors such as ۶TOT and ۴S۰V associated with human orexin۱ and ۲ were considered, respectively. Virtual screening process was performed using the pharmacophoric features of lemborexant and suvorexant using the Zinc database. Virtual screening helps to repurpose already established molecules in a Polypharmacological approach and also it reduces the burden of synthesis. Virtually screened molecules were docked to the active pocket of both receptors, and comparative analyses were performed. Once the reproducibility of binding energy scores and binding modes were validated, the top hit molecules with potential inhibitions against orexin ۱ and ۲ receptor were selected for further evaluations. MEP and FMO analyses of the best docked molecules were calculated by B۳LYP functional and ۶–۳۱۱ G(d,p) levels using GAMESS software. Finally, ADMET analyses were also performed. ZINC۸۴۵۸۷۴۷۲ and ZINC۶۳۷۴۶۵۵۸ were the best docked molecules against orexin-۱ and ۲ receptors, respectively. Here, ZINC۸۴۵۸۷۴۷۲ showed the highest levels of electronegativity and electrophilicity, respectively. ZINC۸۴۵۸۷۴۷۲ was observed as the most reactive molecules. Computational studies confirmed that ZINC۸۴۵۸۷۴۷۲ and ZINC۶۳۷۴۶۵۵۸ molecules showed good orexin-۱ and orexin-۲ antagonists with good receptor binding and electronic properties.

Keywords:

Orexin , Pharmacophore , Virtual screening , Molecular docking , DFT , ADMET