De novo ssRNA Aptamers against the SARS-CoV-2 Main Protease: In Silico Design and Molecular Dynamics Simulation

Herein, we have generated ssRNA aptamers to inhibit SARS-CoV-2 M(pro), a protease necessary for the SARS-CoV-2 coronavirus replication. Because there is no aptamer 3D structure currently available in the databanks for this protein, first, we modeled an ssRNA aptamer using an entropic fragment-based strategy. We refined the initial sequence and 3D structure by using two sequential approaches, consisting of an elitist genetic algorithm and an RNA inverse process. We identified three specific aptamers against SARS-CoV-2 M(pro), called MApta(pro), MApta(pro)-IR1, and MApta(pro)-IR2, with similar 3D conformations and that fall in the dimerization region of the SARS-CoV-2 M(pro) necessary for the enzymatic activity. Through the molecular dynamic simulation and binding free energy calculation, the interaction between the MApta(pro)-IR1 aptamer and the SARS-CoV-2 M(pro) enzyme resulted in the strongest and the highest stable complex; therefore, the ssRNA MApta(pro)-IR1 aptamer was selected as the best potential candidate for the inhibition of SARS-CoV-2 M(pro) and a perspective therapeutic drug for the COVID-19 disease.