Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds

Fischer, André; Sellner, Manuel; Neranjan, Santhosh; Smieško, Martin; Lill, Markus A.

doi:10.3390/ijms21103626

Cited by 142 publications

(109 citation statements)

References 77 publications

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“…Since the release of SARS-CoV-2 M pro structures in apo and inhibitor-bound states, multiple MD simulation and docking studies of this enzyme have already been published. [22][23][24][25][26][27][28] Although a precise determination of the specific protonation states of Cys145 and several histidines in M pro in this pH-sensitive enzyme will be critical to effective and robust computational drug design efforts, these protonation states have not been unequivocally determined.…”

Section: Introductionmentioning

confidence: 99%

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

Pavlova

Lynch

Daidone

et al. 2020

Preprint

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The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nu-cleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored Nδ (HD) and Nϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.

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Section: Introductionmentioning

confidence: 99%

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

Pavlova

Lynch

Daidone

et al. 2020

Preprint

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“…To our knowledge, direct determination of the inhibition e cacy of HIV PIs against SARS-CoV-2 M pro in cell culture has not yet been attempted, although many in silico studies analyzing interaction between SARS-CoV-2 M pro and potential inhibitors were published [20][21][22][23][24][25][26] (Supplementary Table 1). Antiviral assays using lopinavir and ritonavir in Calu-3 cells were previously carried out for MERS-CoV, and the IC 50 for lopinavir, ritonavir and their combination was 11.6, 24.9, and 8.5 µM respectively [3].…”

Section: Discussionmentioning

confidence: 99%

Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2’s main protease

Mahdi

Mótyán

Szojka

et al. 2020

Preprint

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Abstract Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. Atazanavir on the other hand was the only PI to inhibit the viral protease both in cell culture and in our in vitro enzymatic assay. Conclusion Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.

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“…One logical approach to find CoV PLpro inhibitors for COVID-19 is to evaluate previously identified inhibitors of viral enzymes. The most rapid type of assay for screening thousands of compounds is high-throughput screening and virtual screening using molecular docking of such compounds into the binding sites of the enzymes [ 76 , 77 ]. The structure of the complex obtained either by docking or X-ray crystallography can shed light on the modes of binding, for further structure optimization of the inhibitor [ 78 ].…”

Section: Current Development Of Inhibitors Of Cov Plpromentioning

confidence: 99%

Papain-Like Proteases as Coronaviral Drug Targets: Current Inhibitors, Opportunities, and Limitations

Petushkova

Zamyatnin

2020

Pharmaceuticals

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Papain-like proteases (PLpro) of coronaviruses (CoVs) support viral reproduction and suppress the immune response of the host, which makes CoV PLpro perspective pharmaceutical targets. Their inhibition could both prevent viral replication and boost the immune system of the host, leading to the speedy recovery of the patient. Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third CoV outbreak in the last 20 years. Frequent mutations of the viral genome likely lead to the emergence of more CoVs. Inhibitors for CoV PLpro can be broad-spectrum and can diminish present and prevent future CoV outbreaks as PLpro from different CoVs have conservative structures. Several inhibitors have been developed to withstand SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). This review summarizes the structural features of CoV PLpro, the inhibitors that have been identified over the last 20 years, and the compounds that have the potential to become novel effective therapeutics against CoVs in the near future.

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Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds

Cited by 142 publications

References 77 publications

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2’s main protease

Papain-Like Proteases as Coronaviral Drug Targets: Current Inhibitors, Opportunities, and Limitations

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