Prospects for repurposing FDA-approved medications as Omicron spike/ACE-2 protein complex disruptors

Abstract

The interaction of viruses with the host cell surface proteins is a critical step in disease pathogenesis. The interaction of SARS-CoV-2 spike protein and human ACE-2 (Angiotensin-converting enzyme 2) protein, which is similar to the ligand-receptor binding, initiates viral attachment, facilitates cellular viral entry, and subsequent replication in the human body leading to potentially fatal illnesses such as acute respiratory distress syndrome, and multi-organ failure. The Omicron variant, known as B.1.1.529, is a novel SARS-CoV-2 variant of concern, contains thirty distinct mutations, fifteen of which occur in the spike protein. With the high number of mutations in the spike protein, it is more likely to increase transmissibility and increase the ability to cause a severe form of the disease. The variant is believed to affect even the vaccinated individuals. Hence, there is an urgent need to search for more suitable pharmacotherapy to treat this infection. In this view, the study was aimed to screen the existing FDA (Food and Drug Administration)-approved drugs as a potential protein-protein complex disruptor against Omicron spike/ACE-2 protein complex through virtual screening using molecular docking and dynamic simulation. Initially, 2137 small molecules were selected from the FDAapproved drugs database and virtually screened against Omicron spike/ACE-2 complex. Based on higher docking score, interactions with 'hotspot' residues, and binding free energies three drugs namely Floctafenine, Metaraminol and Vilanterol were selected for further molecular dynamics analysis to predict the stability of the complex. Floctafenine complex showed a higher RMSD (Root Mean Square Deviation) value than Omicron spike/ACE-2 protein complex and it reduces the hydrogen bonding interactions between the complex proteins. Floctafenine will play as PPI (proteinprotein interaction) disruptor for virus attachment/cellular entry and act as an initial demonstration for the repurposing of existing small molecules for alternative and cost-effective antiviral therapy for the treatment of disease caused by of Omicron variant of SARS-CoV-2.