Prioritisation of Compounds for 3CLpro Inhibitor Development on SARS-CoV-2 Variants

Abstract

COVID-19 represents a new potentially life-threatening illness caused by severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 pathogen. In 2021, new variants of the virus with multiple key mutations have emerged, such as B.1.1.7, B.1.351, P.1 and B.1.617, and are threatening to render available vaccines or potential drugs ineffective. In this regard, we highlight 3CLpro, the main viral protease, as a valuable therapeutic target that possesses no mutations in the described pandemically relevant variants. 3CLpro could therefore provide trans-variant effectiveness that is supported by structural studies and possesses readily available biological evaluation experiments. With this in mind, we performed a high throughput virtual screening experiment using CmDock and the “In-Stock” chemical library to prepare prioritisation lists of compounds for further studies. We coupled the virtual screening experiment to a machine learning-supported classification and activity regression study to bring maximal enrichment and available structural data on known 3CLpro inhibitors to the prepared focused libraries. All virtual screening hits are classified according to 3CLpro inhibitor, viral cysteine protease or remaining chemical space based on the calculated set of 208 chemical descriptors. Last but not least, we analysed if the current set of 3CLpro inhibitors could be used in activity prediction and observed that the field of 3CLpro inhibitors is drastically under-represented compared to the chemical space of viral cysteine protease inhibitors. We postulate that this methodology of 3CLpro inhibitor library preparation and compound prioritisation far surpass the selection of compounds from available commercial “corona focused libraries”.

Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

“…The druggability of 3CL pro has already been demonstrated in various studies. The mutations in the dominant variants of SARS-CoV-2, such as B.1.1.7 and B.1.617, with higher transmissibility rate were studied and it has been demonstrated that most of the mutations have been found in the receptor binding domains or structural proteins, but no mutation has been reported in 3CL pro so far [38]. Therefore, 3CL pro is an attractive target for anti-COVID-19 drug discovery.…”

Commercial SARS-CoV-2 Targeted, Protease Inhibitor Focused and Protein–Protein Interaction Inhibitor Focused Molecular Libraries for Virtual Screening and Drug Design

“…The pressure on the scientific community to develop a vaccine or drug has never been greater [ 81 ]. Several SARS-CoV-2 proteins have emerged as potential therapeutic targets for drug development, for example, S-protein and the viral proteases 3CL pro and PL pro [ 25 , 82 , 83 , 84 , 85 ]. With the new potential SARS-CoV-2 targets in mind, we decided to evaluate the commercially available SARS-CoV-2-targeted libraries.…”

Repurposing of Drugs for SARS-CoV-2 Using Inverse Docking Fingerprints

“…The complex contains {tert}-butyl ∼{N}-[1-[(2∼{S})-3-cyclohexyl-1-[[(2∼{S},3∼{R})-4-(cyclopropylamino)-3-oxidanyl-4-oxidanylidene-1-[(3∼{R})-2-oxidanylidene-3,4-dihydropyrrol-3-yl]butan-2-yl]amino]-1-oxidanylidene-propan-2-yl]-2-oxidanylidene-pyridin-3-yl]carbamate (OEW), a peptide-like covalent inhibitor (MW = 585.69 g/mol). As described previously ( Jukič et al, 2021 ), this complex comprises the peptidomimetic inhibitor OEW, which occupies all major pockets at the active site of the enzyme, leaving the S1 pocket accessible and the enzyme in the active conformation. After superposition with a reference structure (PDB ID:6LU7), the catalytic binding pocket was defined around Cys145 ( Jin et al, 2020 ).…”

“…, a peptide-like covalent inhibitor (MW 585.69 g/mol). As described previously (Jukič et al, 2021), this complex comprises the peptidomimetic inhibitor OEW, which occupies all major pockets at the active site of the enzyme, leaving the S1 pocket accessible and the enzyme in the active conformation. After superposition with a reference structure (PDB ID:6LU7), the catalytic binding pocket was defined around Cys145 (Jin et al, 2020).…”