Quantum simulations of SARS-CoV-2 main protease Mpro enable high-quality scoring of diverse ligands.
J Comput Aided Mol Des
; 35(9): 963-971, 2021 09.
Article
in English
| MEDLINE | ID: covidwho-1406168
ABSTRACT
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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Coronavirus 3C Proteases
Type of study:
Prognostic study
Language:
English
Journal:
J Comput Aided Mol Des
Journal subject:
Molecular Biology
/
Biomedical Engineering
Year:
2021
Document Type:
Article
Affiliation country:
S10822-021-00412-7
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