Optimization strategy of single-digit nanomolar cross-class inhibitors of mammalian and protozoa cysteine proteases
Copyright © 2020 Elsevier Inc. All rights reserved..
Cysteine proteases (CPs) are involved in a myriad of actions that include not only protein degradation, but also play an essential biological role in infectious and systemic diseases such as cancer. CPs also act as biomarkers and can be reached by active-based probes for diagnostic and mechanistic purposes that are critical in health and disease. In this paper, we present the modulation of a CP panel of parasites and mammals (Trypanosoma cruzi cruzain, LmCPB, CatK, CatL and CatS), whose inhibition by nitrile peptidomimetics allowed the identification of specificity and selectivity for a given CP. The activity cliffs identified at the CP inhibition level are useful for retrieving trends through multiple structure-activity relationships. For two of the cruzain inhibitors (10g and 4e), both enthalpy and entropy are favourable to Gibbs binding energy, thus overcoming enthalpy-entropy compensation (EEC). Group contribution of individual molecular modification through changes in enthalpy and entropy results in a separate partition on the relative differences of Gibbs binding energy (ΔΔG). Overall, this study highlights the role of CPs in polypharmacology and multi-target screening, which represents an imperative trend in the actual drug discovery effort.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:101 |
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| Enthalten in: |
Bioorganic chemistry - 101(2020) vom: 10. Aug., Seite 104039 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cianni, Lorenzo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.03.2021 Date Revised 18.03.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2020.104039 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM312069596 |
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| 100 | 1 | |a Cianni, Lorenzo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Optimization strategy of single-digit nanomolar cross-class inhibitors of mammalian and protozoa cysteine proteases |
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| 500 | |a Date Revised 18.03.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier Inc. All rights reserved. | ||
| 520 | |a Cysteine proteases (CPs) are involved in a myriad of actions that include not only protein degradation, but also play an essential biological role in infectious and systemic diseases such as cancer. CPs also act as biomarkers and can be reached by active-based probes for diagnostic and mechanistic purposes that are critical in health and disease. In this paper, we present the modulation of a CP panel of parasites and mammals (Trypanosoma cruzi cruzain, LmCPB, CatK, CatL and CatS), whose inhibition by nitrile peptidomimetics allowed the identification of specificity and selectivity for a given CP. The activity cliffs identified at the CP inhibition level are useful for retrieving trends through multiple structure-activity relationships. For two of the cruzain inhibitors (10g and 4e), both enthalpy and entropy are favourable to Gibbs binding energy, thus overcoming enthalpy-entropy compensation (EEC). Group contribution of individual molecular modification through changes in enthalpy and entropy results in a separate partition on the relative differences of Gibbs binding energy (ΔΔG). Overall, this study highlights the role of CPs in polypharmacology and multi-target screening, which represents an imperative trend in the actual drug discovery effort | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cysteine protease inhibitors | |
| 650 | 4 | |a Differential scanning calorimetry | |
| 650 | 4 | |a Isothermal titration calorimetry | |
| 650 | 4 | |a Matched molecular pair analysis | |
| 650 | 4 | |a Molecular dynamics simulation | |
| 650 | 4 | |a Structure activity relationships | |
| 650 | 7 | |a Cysteine Proteases |2 NLM | |
| 650 | 7 | |a EC 3.4.- |2 NLM | |
| 700 | 1 | |a Rocho, Fernanda Dos Reis |e verfasserin |4 aut | |
| 700 | 1 | |a Rosini, Fabiana |e verfasserin |4 aut | |
| 700 | 1 | |a Bonatto, Vinícius |e verfasserin |4 aut | |
| 700 | 1 | |a Ribeiro, Jean F R |e verfasserin |4 aut | |
| 700 | 1 | |a Lameira, Jerônimo |e verfasserin |4 aut | |
| 700 | 1 | |a Leitão, Andrei |e verfasserin |4 aut | |
| 700 | 1 | |a Shamim, Anwar |e verfasserin |4 aut | |
| 700 | 1 | |a Montanari, Carlos A |e verfasserin |4 aut | |
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