Ivermectin and Doxycycline combination as a promising anti-viral drug candidate: an in-silico and DFT study

In contemporary area of medical research, repurposing of drugs has emerged as a promising strategy in drug discovery against viral infections in individual or in combination modes. The 3-chymotrypsin-like protease (3CL^pro) plays an essential role in mediating viral replication in the human body. It is key for developing potent and selective inhibitors for inhibiting viral replication. In this work, we have studied the possible efficacy of two popularly used repurposed drugs: Ivermectin and Doxycycline in their individual and combination modes as anti-viral agents. Density functional theory (DFT) was used to establish the chemical reactivity of the proposed drugs. Molecular electrostatic potential (MEP) and charge distribution analysis were used to check the antiviral effectivity. The study included the characteristics of the drug: 3CL^pro interactions through in-silico molecular docking and molecular dynamic (MD) simulation approaches through various thermodynamic parameters (E_pot, T, V, D, R_g, SASA energy) for identifying better reactiveness of both Ivermectin and Doxycycline in their individual and combination modes. Individually, Ivermectin showed a good binding affinity (-6.9 kcal/mol) over Doxycycline (-6.4 kcal/mol). In combination mode, Ivermectin + Doxycycline has showed a significant enhancement in the binding affinity (-7.4 kcal/mol). Our Insilco output has established that both individual and combination modes of prescribed repurposed drugs: Ivermectin and Doxycycline can be used as antiviral target towards the infections caused by 3CL^pro protease.