Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors

Kitamura, Naoya; Sacco, M.; Ma, Chunlong; Hu, Yanmei; Townsend, Julia Alma; Meng, Xiangzhi; Zhang, Fu‐Shun; Zhang, Xiujun; Ba, Mandy; Szeto, Tommy; Kukuljac, Adis; Marty, Michael T.; Schultz, D.; Cherry, Sara; Xiang, Yan; Chen, Yu; Wang, Junyang

doi:10.1021/acs.jmedchem.1c00509

Cited by 113 publications

(124 citation statements)

References 36 publications

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“…The antiviral assay was performed as previously described 21 . Calu-3 cells (ATCC, HTB-55) were plated in 384 well plates and grown in minimal Eagle’s medium supplemented with 1% non-essential amino acids, 1% penicillin/streptomycin, and 10% FBS.…”

Section: Mathods and Materialsmentioning

confidence: 99%

Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays

Tan

Choza

et al. 2022

Acta Pharmaceutica Sinica B

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Section: Mathods and Materialsmentioning

confidence: 99%

Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays

Tan

Choza

et al. 2022

Acta Pharmaceutica Sinica B

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“…In parallel, it is reported that among candidates in clinical trials, such as protease inhibitor GC376 and ketone-based inhibitors showed promising action due to their interaction with dyad catalytic (His 41 and Cys145) [74][75][76].…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity of Metabolites from Peruvian Plants against SARS-CoV-2: An In Silico Approach

et al. 2021

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(1) Background: The COVID-19 pandemic lacks treatments; for this reason, the search for potential compounds against therapeutic targets is still necessary. Bioinformatics tools have allowed the rapid in silico screening of possible new metabolite candidates from natural resources or repurposing known ones. Thus, in this work, we aimed to select phytochemical candidates from Peruvian plants with antiviral potential against three therapeutical targets of SARS-CoV-2. (2) Methods: We applied in silico technics, such as virtual screening, molecular docking, molecular dynamics simulation, and MM/GBSA estimation. (3) Results: Rutin, a compound present in Peruvian native plants, showed affinity against three targets of SARS-CoV-2. The molecular dynamics simulation demonstrated the high stability of receptor–ligand systems during the time of the simulation. Our results showed that the Mpro-Rutin system exhibited higher binding free energy than PLpro-Rutin and N-Rutin systems through MM/GBSA analysis. (4) Conclusions: Our study provides insight on natural metabolites from Peruvian plants with therapeutical potential. We found Rutin as a potential candidate with multiple pharmacological properties against SARS-CoV-2.

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“…Most of the established interactions between each compound and the amino acid residues of the active site (Figure 5) could be overlaid on the structure of the co-crystalized inhibitor (Figure 5D,H) [41]. The binding modes of S and R-isomers of compound 1 were slightly different.…”

Section: Ensemble Dockingmentioning

confidence: 99%

Bioguided Isolation of Cyclopenin Analogues as Potential SARS-CoV-2 Mpro Inhibitors from Penicillium citrinum TDPEF34

et al. 2021

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SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease Mpro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential Mpro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 Mpro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards Mpro, with an IC50 values range of 0.36–0.89 µM comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent Mpro inhibitors.

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Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors

Cited by 113 publications

References 36 publications

Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays

Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays

Antiviral Activity of Metabolites from Peruvian Plants against SARS-CoV-2: An In Silico Approach

Bioguided Isolation of Cyclopenin Analogues as Potential SARS-CoV-2 Mpro Inhibitors from Penicillium citrinum TDPEF34

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