Molecular dynamics simulations of ASC09, ritonavir, lopinavir and darunavir with the COVID-19 protease

Abstract

Given the novelty of SARS-CoV-2 infection (COVID-19), and the lack of proven therapies, a wide variety of strategies are being employed to combat COVID-19 pandemic. Many of these emerging strategies rely on repurposing existing drugs and their mechanistic approaches that are effective against either similar viral infections or the serious symptoms that are caused by COVID-19. The recently solved issue of the crystal structure of the COVID-19 protease has made elucidating the structure–activity relationship feasible. The interaction of ASC09, ritonavir, lopinavir and darunavir with COVID-19 protease was simulated using the Site Finder module, molecular docking and molecular dynamics (MD). Analysis of the MD trajectories has provided the ligand/receptor interaction fingerprints, combining information on the crucial receptor residues and frequency of the ligand/residue contacts. The contact frequencies and the contact maps suggest that for all studied antiviral drugs, the interactions with Gln 107, Pro 108, Gln 110 and His 246 are an important factor for drugs affinities toward the COVID-19 protease. However, the leading interactions with Arg 105, Phe 134, Glu 240, Thr 243, Asp 245 or Phe 294 also significantly contribute to the ligand/receptor interplay and, in particular, differentiate their binding affinities toward COVID-19 protease.