Quantum simulations of SARS-CoV-2 main protease Mpro enable high-quality scoring of diverse ligands.
Yuhang WangSruthi MurlidaranDavid A PearlmanPublished in: Journal of computer-aided molecular design (2021)
The COVID-19 pandemic has led to unprecedented efforts to identify drugs that can reduce its associated morbidity/mortality rate. Computational chemistry approaches hold the potential for triaging potential candidates far more quickly than their experimental counterparts. These methods have been widely used to search for small molecules that can inhibit critical proteins involved in the SARS-CoV-2 replication cycle. An important target is the SARS-CoV-2 main protease Mpro, an enzyme that cleaves the viral polyproteins into individual proteins required for viral replication and transcription. Unfortunately, standard computational screening methods face difficulties in ranking diverse ligands to a receptor due to disparate ligand scaffolds and varying charge states. Here, we describe full density functional quantum mechanical (DFT) simulations of Mpro in complex with various ligands to obtain absolute ligand binding energies. Our calculations are enabled by a new cloud-native parallel DFT implementation running on computational resources from Amazon Web Services (AWS). The results we obtain are promising: the approach is quite capable of scoring a very diverse set of existing drug compounds for their affinities to M pro and suggest the DFT approach is potentially more broadly applicable to repurpose screening against this target. In addition, each DFT simulation required only ~ 1 h (wall clock time) per ligand. The fast turnaround time raises the practical possibility of a broad application of large-scale quantum mechanics in the drug discovery pipeline at stages where ligand diversity is essential.
Keyphrases
- sars cov
- density functional theory
- molecular dynamics
- drug discovery
- respiratory syndrome coronavirus
- healthcare
- monte carlo
- primary care
- quality improvement
- mental health
- cardiovascular events
- human health
- transcription factor
- molecular docking
- emergency department
- type diabetes
- anti inflammatory
- risk factors
- cardiovascular disease
- coronary artery disease
- drug induced
- molecular dynamics simulations
- binding protein
- solar cells
- quantum dots