Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

Although researchers have been working tirelessly since the COVID-19 outbreak, there is yet no effective drug found to directly treat the disease. Given the slow pace and substantial costs of new drug discovery and development, repurposing of existing drugs for the ongoing disease becomes an attractive proposition. In a recent study, a high-throughput x-ray crystallographic screen has been performed for the drugs which have been approved or are in clinical trials. 37 compounds have been identified from drug libraries, which bind to the SARS-CoV-2 main protease (3CLpro). In the current study, we use molecular dynamics simulation and an ensemble-based free energy approach, namely, enhanced sampling of molecular dynamics with approximation of continuum solvent (ESMACS), to investigate a subset of the aforementioned compounds. The drugs studied here are highly diverse, interacting with different binding sites and/or subsites of 3CLpro. ESMACS gives precise and reproducible free energy predictions, which agree well with experimental measurement. Our study also provides detailed energetic insight into the nature of drug−protein binding, which would shed light on the design and discovery of potential drugs.