Exploring protein hotspots by optimized fragment pharmacophores

Bajusz, Dávid; Wade, Warren S.; Satała, Grzegorz; Bojarski, Andrzej J.; Ilaš, Janez; Ebner, Jessica; Grebien, Florian; Papp, Henrietta; Jakab, Ferenc; Douangamath, A.; Fearon, D.; Delft, F. von; Schuller, M.; Ahel, Ivan; Wakefield, Amanda; Vajda, Sándor; Gerencsér, János; Pallai, Peter V.; Keserü, György M.

doi:10.1038/s41467-021-23443-y

Cited by 39 publications

(47 citation statements)

References 60 publications

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“…Therefore, it is imperative to develop specific and safe antiviral drugs against SARS-CoV-2. The global research community has launched diverse de novo efforts, including worldwide collaborations such as the COVID Moonshot consortium for the discovery of SARS-CoV-2 main protease inhibitors [8], and large fragment screens against multiple viral targets [9,10] using innovative compound libraries [11,12]. In addition to bottom-up approaches, existing chemical entities can be further exploited by repurposing approved drugs [13,14], clinical trial drug candidates or natural products.…”

Section: Introductionmentioning

confidence: 99%

Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

et al. 2021

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The protracted global COVID-19 pandemic urges the development of new drugs against the causative agent SARS-CoV-2. The clinically used glycopeptide antibiotic, teicoplanin, emerged as a potential antiviral, and its efficacy was improved with lipophilic modifications. This prompted us to prepare new lipophilic apocarotenoid conjugates of teicoplanin, its pseudoaglycone and the related ristocetin aglycone. Their antiviral effect was tested against SARS-CoV-2 in Vero E6 cells, using a cell viability assay and quantitative PCR of the viral RNA, confirming their micromolar inhibitory activity against viral replication. Interestingly, two of the parent apocarotenoids, bixin and β-apo-8′carotenoic acid, exerted remarkable anti-SARS-CoV-2 activity. Mechanistic studies involved cathepsin L and B, as well as the main protease 3CLPro, and the results were rationalized by computational studies. Glycopeptide conjugates show dual inhibitory action, while apocarotenoids have mostly cathepsin B and L affinity. Since teicoplanin is a marketed antibiotic and the natural bixin is an approved, cheap and widely used red colorant food additive, these readily available compounds and their conjugates as potential antivirals are worthy of further exploration.

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Section: Introductionmentioning

confidence: 99%

Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

et al. 2021

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“…Very recently, Bajusz et al. have reported a fragment, SX013, that blocks the SARS‐CoV‐2 replication in Vero E6 cells with an EC 50 of 304 μM, [46] which is double of that for F01 in Vero‐81 cells. The ligand efficiency of F01 is 0.29–0.30 kcal mol −1 heavy atom −1 showing that F01 is a good fragment lead and deserved to be optimized in order to increase its potency and other drug related properties.…”

Section: Resultsmentioning

confidence: 99%

NMR Spectroscopy of the Main Protease of SARS‐CoV‐2 and Fragment‐Based Screening Identify Three Protein Hotspots and an Antiviral Fragment

et al. 2021

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The main protease (3CLp) of the SARS-CoV-2, the causative agent for the COVID-19 pandemic,isone of the main targets for drug development. To be active,3 CLp relies on ac omplex interplay between dimerization, active site flexibility,a nd allosteric regulation. The deciphering of these mechanisms is ac rucial step to enable the search for inhibitors.I n this context, using NMR spectroscopy, we studied the conformation of dimeric 3CLp from the SARS-CoV-2 and monitored ligand binding,based on NMR signal assignments. We performed af ragment-based screening that led to the identification of 38 fragment hits.T heir binding sites showed three hotspots on 3CLp,t wo in the substrate binding pocket and one at the dimer interface. F01 is anon-covalent inhibitor of the 3CLp and has antiviral activity in SARS-CoV-2 infected cells.T his study sheds light on the complex structure-function relationships of 3CLp and constitutes astrong basis to assist in developing potent 3CLp inhibitors.

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“…Such strategy helps overcome drug discovery challenges that limit pharmacokinetic performances and drug formulation option. For instance, the prodrugs Ivemend and Gilenya were reported to improve solubility and enhance permeation, respectively ( 5 ). Therefore, a number of prodrugs were first collected by reviewing PubMed literatures ( 34 ) using various keywords such as ‘prodrug’, ‘pro-drug’, etc.…”

Section: Prodrugsmentioning

confidence: 99%

“…Drug discovery is promoted by not only the knowledge of drugs ( 1 ) and their therapeutic targets ( 2–4 ), but also the comparative data with respect to other bioactive agents and other targets. Such comparative data include the knowledge of poor binders or non-binders of individual target that are useful for developing drug discovery tool of enhanced performance ( 5–7 ); the information of prodrugs that facilitates drug design by improving pharmacokinetic/pharmacodynamic features ( 8 ); the co-targets of therapeutic targets that facilitate the investigations of multi-target strategies ( 9 ), off-target ( 10 , 11 ) & undesired effect ( 9 ); the collective structure-activity landscapes of drugs against individual target that reveal important pharmaceutical features such as activity cliffs ( 12 ); and the drugs’ profiles of their drug-like properties that provide drug-likeness landscapes of the explored bioactive chemical space for therapeutic targets ( 13 ). Particularly, there is a rapid trend of the discovery of Artificial Intelligence (AI) tools for the drug discovery ( 14 , 15 ), including the AI tools for identifying bioactive compounds, and the construction of such tools requires data of poor binders and non-binders of a specific target ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents

Zhou

Zhang

Lian

et al. 2021

Nucleic Acids Research

411

241

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Drug discovery relies on the knowledge of not only drugs and targets, but also the comparative agents and targets. These include poor binders and non-binders for developing discovery tools, prodrugs for improved therapeutics, co-targets of therapeutic targets for multi-target strategies and off-target investigations, and the collective structure-activity and drug-likeness landscapes of enhanced drug feature. However, such valuable data are inadequately covered by the available databases. In this study, a major update of the Therapeutic Target Database, previously featured in NAR, was therefore introduced. This update includes (a) 34 861 poor binders and 12 683 non-binders of 1308 targets; (b) 534 prodrug-drug pairs for 121 targets; (c) 1127 co-targets of 672 targets regulated by 642 approved and 624 clinical trial drugs; (d) the collective structure-activity landscapes of 427 262 active agents of 1565 targets; (e) the profiles of drug-like properties of 33 598 agents of 1102 targets. Moreover, a variety of additional data and function are provided, which include the cross-links to the target structure in PDB and AlphaFold, 159 and 1658 newly emerged targets and drugs, and the advanced search function for multi-entry target sequences or drug structures. The database is accessible without login requirement at: https://idrblab.org/ttd/.

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Exploring protein hotspots by optimized fragment pharmacophores

Cited by 39 publications

References 60 publications

Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication

NMR Spectroscopy of the Main Protease of SARS‐CoV‐2 and Fragment‐Based Screening Identify Three Protein Hotspots and an Antiviral Fragment

Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents

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