Metadynamics-based enhanced sampling protocol for virtual screening: case study for 3CLpro protein for SARS-CoV-2

In recent times, computational methods played an important role in the down selection of chemical compounds, which could be a potential drug candidate with a high affinity to target proteins. However, the screening methodologies, including docking, often fails to identify the most effective compound, which could be a ligand for the target protein. To solve that, here we have integrated meta-dynamics, an enhanced sampling molecular simulation method, with all-atom molecular dynamics to determine a specific compound that could target the main protease of novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). This combined computational approach uses the enhanced sampling to explore the free energy surface associated with the protein's binding site (including the ligand) in an explicit solvent. We have implemented this method to find new chemical entities that exhibit high specificity of binding to the 3-chymotrypsin-like cysteine protease (3CLpro) present in the SARS-CoV-2 and segregated to the most strongly bound ligands based on free energy and scoring functions (defined and implemented) from a set of 17 ligands which were prescreened for synthesizability and druggability. Additionally, we have compared these 17 ligands' affinities against controls, N3 and 13b alpha-ketoamide inhibitors, for which experimental crystal structures are available. Based on our results and analysis from the combined molecular simulation approach, we could identify the best compound which could be further taken as a potential candidate for experimental validation. Communicated by Ramaswamy H. Sarma

Automated summary

In this study, computational methods were used to identify a specific compound targeting the main protease of SARS-COV-2. By integrating meta-dynamics with molecular dynamics, an enhanced sampling approach was applied to explore the binding site's free energy surface. The analysis led to the identification of potential drug candidates with high specificity for the target protein, based on free energy and scoring functions compared to control inhibitors.