Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection

Vandyck, Koen; Deval, Jérôme

doi:10.1016/j.coviro.2021.04.006

Cited by 121 publications

(100 citation statements)

References 41 publications

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“… 38 In April 2021, Pfizer revealed the orally available M pro inhibitor PF-07321332, which is a short substrate analogue featuring a C-terminal nitrile warhead. 39 Very recently, a cyclic peptide has been reported, which binds to SARS-CoV-2 M pro without forming a covalent bond. 40 With an IC 50 value of about 160 µM, however, the activity of this compound is many orders of magnitudes below those of substrate-based analogues with warheads.…”

mentioning

confidence: 99%

Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors

Ullrich

Sasi

Mahawaththa

et al. 2021

Bioorganic & Medicinal Chemistry Letters

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confidence: 99%

Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors

Ullrich

Sasi

Mahawaththa

et al. 2021

Bioorganic & Medicinal Chemistry Letters

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“…Nowadays, The M pro of SARS-CoV-2 has become one of the most promising targets for new drugs. The M pro inhibitor PF-07321332 from Pfizer has entered a Phase I clinical study [ 31 ]. Carboline and quinoline molecules were reported to possess powerful antiviral bioactivities.…”

Section: Discussionmentioning

confidence: 99%

In silico Discovery of SARS-CoV-2 Main Protease Inhibitors From the Carboline and Quinoline Database

2021

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Aim: SARS-CoV-2 caused more than 3.8 million deaths according to the WHO. In this urgent circumstance, we aimed at screening out potential inhibitors targeting the main protease of SARS-CoV-2. Materials & methods: An in-house carboline and quinoline database including carboline, quinoline and their derivatives was established. A virtual screening in carboline and quinoline database, 50 ns molecular dynamics simulations and molecular mechanics Poisson−Boltzmann surface area calculations were carried out. Results: The top 12 molecules were screened out preliminarily. The molecular mechanics Poisson−Boltzmann surface area ranking showed that p59_7m, p12_7e, p59_7k stood out with the lowest binding energies of -24.20, -17.98, -17.67 kcal/mol, respectively. Conclusion: The study provides powerful in silico results that indicate the selected molecules are valuable for further evaluation as SARS-CoV-2 main protease inhibitors.

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“…It received an emergency use authorization from the FDA, although some studies have shown that remdesivir has no benefits compared to placebo in treating SARS-CoV-2 infection [6]. Some other drugs are still in clinical trials, such as AT-527, EIDD-2801, favipiravir, PF-07321332, PF-07304814, and niclosamide [4,[7][8][9][10]. However, all the drugs mentioned are focused on either RdRp or M pro .…”

Section: Introductionmentioning

confidence: 99%

“…The limited bioavailability of some potential anti-SARS-CoV-2 drugs, such as PF-00835231 and GC-376, has diminished their efficacy in the clinical trials [10]. Therefore, zinc oxide nanoparticles (ZnO NPs) were employed in this study as a drug carrier [13] to enhance the bioavailability and efficacy of the selected compound.…”

Section: Introductionmentioning

confidence: 99%

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity

Hamdy

Fayed

Mostafa

et al. 2021

IJMS

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Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4’-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand–protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1–5 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 µM and Mpro inhibition activity with IC50 0.013 µM, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 µM, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies.

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Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection

Cited by 121 publications

References 41 publications

Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors

Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors

In silico Discovery of SARS-CoV-2 Main Protease Inhibitors From the Carboline and Quinoline Database

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity

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