Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface

After over two years of living with Covid-19 and hundreds of million cases worldwide there is still an unmet need to find proper treatments for the novel coronavirus, due also to the rapid mutation of its genome. In this context, a drug repositioning study has been performed, using in silico tools targeting Delta Spike protein/ACE2 interface. To this aim, it has been virtually screened a library composed by 4388 approved drugs through a deep learning-based QSAR model to identify protein-protein interactions modulators for molecular docking against Spike receptor binding domain (RBD). Binding energies of predicted complexes were calculated by Molecular Mechanics/Generalized Born Surface Area from docking and molecular dynamics simulations. Four out of the top twenty ranking compounds showed stable binding modes on Delta Spike RBD and were evaluated also for their effectiveness against Omicron. Among them an antihistaminic drug, fexofenadine, revealed very low binding energy, stable complex, and interesting interactions with Delta Spike RBD. Several antihistaminic drugs were found to exhibit direct antiviral activity against SARS-CoV-2 in vitro, and their mechanisms of action is still debated. This study not only highlights the potential of our computational methodology for a rapid screening of variant-specific drugs, but also represents a further tool for investigating properties and mechanisms of selected drugs.

Automated summary

After over two years of living with Covid-19 and the rapid mutation of its genome, there is still a need to find proper treatments for the novel coronavirus. A drug repositioning study was conducted using in silico tools to target the Delta Spike protein/ACE2 interface. Virtual screening of approved drugs identified four compounds that showed stable binding modes on Delta Spike RBD and were evaluated for effectiveness against Omicron. Among them, fexofenadine, an antihistamine drug, demonstrated low binding energy, stable complex, and interesting interactions with Delta Spike RBD. The study highlights the potential of computational methodology for rapid screening of variant-specific drugs and provides a tool for investigating properties and mechanisms of selected drugs.