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Mol Divers . Repurposing the in-house generated Alzheimer's disease targeting molecules through computational and preliminary in-vitro studies for the management of SARS-coronavirus-2

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  • Mol Divers . Repurposing the in-house generated Alzheimer's disease targeting molecules through computational and preliminary in-vitro studies for the management of SARS-coronavirus-2

    Mol Divers


    . 2023 Sep 25.
    doi: 10.1007/s11030-023-10717-4. Online ahead of print. Repurposing the in-house generated Alzheimer's disease targeting molecules through computational and preliminary in-vitro studies for the management of SARS-coronavirus-2

    Gourav Singh # 1 , Jobin Thomas # 2 , Sahil Wadhawa 1 , Anurag Kashyap 1 , Syed Ajijur Rahaman 1 , Subhomoi Borkotoky 3 4 , Agnisha Datta 5 , Gireesh Kumar Singh 6 , Indubhusan Mishra 7 , Geeta Rai 5 , Jitendra Satija 2 , Vikash Kumar Dubey 3 , Gyan Modi 8



    AffiliationsAbstract

    Covid-19 was declared a world pandemic. Recent studies demonstrated that Covid-19 impairs CNS activity by crossing the blood-brain barrier and ensuing cognitive impairment. In this study, we have utilized Covid-19 main protease (Mpro) as a biological target to repurpose our previously reported multifunctional compounds targeting Alzheimer's disease. Molecular docking, spatial orientation, molecular dynamics simulation, MM-GBSA energy calculation, and DFT studies were carried out with these molecules. Among all the compounds, F27, F44, and F56 exhibited higher binding energy (- 8.03, - 8.65, and - 8.68 kcal/mol, respectively) over the co-crystal ligand O6K (- 7.00 kcal/mol). In MD simulation, compounds F27, F44, and F56 could make a stable complex with Mpro target throughout the simulation. The compounds were synthesized following reported methods and subjected for cytotoxicity, and assessment of their capability to cross the blood-brain barrier in PAMPA assay, and antioxidant property evaluation through DPPH assay. The compounds F27, F44, and F56 exhibited cytocompatibility with the SiHA cell line and also displayed significant antioxidant properties with IC50 = 45.80 ± 0.27 μM, 44.42 ± 0.30 μM, and 42.74 ± 0.23 μM respectively. In the PAMPA assays, the permeability coefficient (Pe) value of F27, F44, and F56 lies in the acceptable range (Pe > 4). The results of the computational and preliminary in-vitro studies strongly corroborate the potential of F27, F44, and F56 as a lead for further optimization in treating the CNS complications associated with Covid-19.

    Keywords: Alzheimer’s disease; Antioxidant; Covid-19; DFT; Molecular dynamics; Mpro; PAMPA.

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