Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease.
Shunzhou WanAgastya P BhatiAlexander D WadeDario AlfèPeter V CoveneyPublished in: Molecular systems design & engineering (2021)
Although researchers have been working tirelessly since the COVID-19 outbreak, so far only three drugs - remdesivir, ronapreve and molnupiravir - have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the matter, repurposing of existing drugs for the ongoing disease is an attractive proposition. In a recent study, a high-throughput X-ray crystallographic screen was performed for a selection of drugs which have been approved or are in clinical trials. Thirty-seven compounds have been identified from drug libraries all of which bind to the SARS-CoV-2 main protease (3CL pro ). 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 3CL pro . The predicted free energies are compared with experimental results wherever they are available and they are found to be in excellent agreement. Our study also provides detailed energetic insights into the nature of the associated drug-protein binding, in turn shedding light on the design and discovery of potential drugs.
Keyphrases
- sars cov
- high throughput
- molecular dynamics
- clinical trial
- molecular dynamics simulations
- drug discovery
- respiratory syndrome coronavirus
- drug induced
- randomized controlled trial
- density functional theory
- machine learning
- small molecule
- computed tomography
- magnetic resonance
- climate change
- molecular docking
- binding protein
- deep learning
- quantum dots
- human health
- ionic liquid
- amino acid
- urinary incontinence