Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization

Sarno, Veronica Di; Lauro, Gianluigi; Musella, Simona; Ciaglia, Tania; Vestuto, Vincenzo; Sala, Marina; Scala, Maria Carmina; Smaldone, Gerardina; Matteo, Francesca Di; Novi, Sara; Tecce, Mario Felice; Moltedo, Ornella; Bifulco, Giuseppe; Campiglia, Pietro; Gómez-Monterrey, Isabel; Snoeck, Robert; Andrei, Gracíela; Ostacolo, Carmine; Bertamino, Alessia

doi:10.1016/j.ejmech.2021.113863

Cited by 29 publications

(31 citation statements)

References 51 publications

(66 reference statements)

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“…A tryptophan-containing dipeptide, compound 54 , was recently reported as a dual inhibitor of SARS-CoV-2 M pro and PL pro . 89 Compound 54 inhibited M pro and PL pro with IC 50 values of 1.72 and 0.67 μM, respectively, while it had no binding to the viral spike protein ( K D > 25 μM). In the antiviral assay, compound 54 inhibited two SARS-CoV-2 clinical isolates, UC-1074 and UC-1075, with EC 50 values of 0.32 and 1.37 μM, respectively.…”

Section: Sars-cov-2 Pl Pro Inhibitorsmentioning

confidence: 97%

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Tan

Jadhav

et al. 2022

J. Med. Chem.

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SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PL pro ) mediates the cleavage of viral polyprotein and modulates the host’s innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PL pro inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PL pro inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PL pro inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PL pro inhibitors to the clinic.

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Section: Sars-cov-2 Pl Pro Inhibitorsmentioning

confidence: 97%

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Tan

Jadhav

et al. 2022

J. Med. Chem.

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“…All selected RBD domains were then aligned to the wild type spike protein in complex with ACE-2, by using Pymol. 25 …”

Section: Methodsmentioning

confidence: 99%

CROMATIC: Cross-Relationship Map of Cavities from Coronaviruses

Siragusa

Menna

Buratta

et al. 2022

J. Chem. Inf. Model.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 disease, has rapidly imposed an urgent need to identify effective drug candidates. In this context, the high resolution and non-redundant beta-Coronavirus protein cavities database is pivotal to help virtual screening protocols. Furthermore, the cross-relationship among cavities can lead to highlighting multitarget therapy chances. Here, we first collect all protein cavities on SARS-CoV-2, SARS-CoV, and MERS-CoV X-ray structures, and then, we compute a similarity map by using molecular interaction fields (MIFs). All the results come together in CROMATIC (CROss-relationship MAp of CaviTIes from Coronaviruses). CROMATIC encloses both a comprehensive and a non-redundant version of the cavities collection and a similarity map revealing, on the one hand, cavities that are conserved among the three Coronaviruses and, on the other hand, unexpected similarities among cavities that can represent a key starting point for multitarget therapy strategies. Similarity analysis was also performed for the available structures of SARS-CoV-2 spike variants, linking sequence mutations to three-dimensional interaction alterations. The CROMATIC repository is freely available to the scientific community at .

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“…Even if many molecules have been shown to bind to M pro [19] and inhibit its activity, and even if a molecule is currently in phase III clinical trial for this purpose (PF-07321332, from Pfizer [20,21]), no drug has already been approved by the European Medicinal Agency for the treatment of SARS-CoV-2 (also called "COVID-19"). Computational methods have already proven to be beneficial in the research for new potential inhibitors for M pro , as the literature witnesses [22,23]. In this work, we decided to implement a molecular-docking-based approach relying on the programs GOLD, Glide, and PLANTS.…”

Section: Introductionmentioning

confidence: 99%

Re-Exploring the Ability of Common Docking Programs to Correctly Reproduce the Binding Modes of Non-Covalent Inhibitors of SARS-CoV-2 Protease Mpro

et al. 2022

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In the latest few decades, molecular docking has imposed itself as one of the most used approaches for computational drug discovery. Several docking benchmarks have been published, comparing the performance of different algorithms in respect to a molecular target of interest, usually evaluating their ability in reproducing the experimental data, which, in most cases, comes from X-ray structures. In this study, we elucidated the variation of the performance of three docking algorithms, namely GOLD, Glide, and PLANTS, in replicating the coordinates of the crystallographic ligands of SARS-CoV-2 main protease (Mpro). Through the comparison of the data coming from docking experiments and the values derived from the calculation of the solvent exposure of the crystallographic ligands, we highlighted the importance of this last variable for docking performance. Indeed, we underlined how an increase in the percentage of the ligand surface exposed to the solvent in a crystallographic complex makes it harder for the docking algorithms to reproduce its conformation. We further validated our hypothesis through molecular dynamics simulations, showing that the less stable protein–ligand complexes (in terms of root-mean-square deviation and root-mean-square fluctuation) tend to be derived from the cases in which the solvent exposure of the ligand in the starting system is higher.

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Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization

Cited by 29 publications

References 51 publications

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

CROMATIC: Cross-Relationship Map of Cavities from Coronaviruses

Re-Exploring the Ability of Common Docking Programs to Correctly Reproduce the Binding Modes of Non-Covalent Inhibitors of SARS-CoV-2 Protease Mpro

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