Identification of noncovalent proteasome inhibitors with high selectivity for chymotrypsin-like activity by a multistep structure based virtual screening
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Carmen Di Giovanni
- Roberta Ettari
- Serena Sarno
- Archimede Rotondo
- Alessandra Bitto
- Francesco Squadrito
- Domenica Altavilla
- Tanja Schirmeister
- Ettore Novellino
- Silvana Grasso
- Maria Zappala
- Antonio Lavecchia
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000382269700049&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.ejmech.2016.05.049
- eISSN
- 1768-3254
- Externe Identifier
- Clarivate Analytics Document Solution ID: DU5RT
- PubMed Identifier: 27318981
- ISSN
- 0223-5234
- Zeitschrift
- EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
- Schlüsselwörter
- Proteasome inhibitors
- Non-covalent
- Peptide scaffold
- Docking studies
- Virtual screening
- Paginierung
- 578 - 591
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Titel
- Identification of noncovalent proteasome inhibitors with high selectivity for chymotrypsin-like activity by a multistep structure based virtual screening
- Sub types
- Article
- Ausgabe der Zeitschrift
- 121
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Carmen Di Giovanni
- Roberta Ettari
- Serena Sarno
- Archimede Rotondo
- Alessandra Bitto
- Francesco Squadrito
- Domenica Altavilla
- Tanja Schirmeister
- Ettore Novellino
- Silvana Grasso
- Maria Zappalà
- Antonio Lavecchia
- DOI
- 10.1016/j.ejmech.2016.05.049
- ISSN
- 0223-5234
- Zeitschrift
- European Journal of Medicinal Chemistry
- Sprache
- en
- Paginierung
- 578 - 591
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.ejmech.2016.05.049
- Datum der Datenerfassung
- 2019
- Titel
- Identification of noncovalent proteasome inhibitors with high selectivity for chymotrypsin-like activity by a multistep structure-based virtual screening
- Ausgabe der Zeitschrift
- 121
Data source: Crossref
- Abstract
- Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors, e.g. carfilzomib, used in cancer therapy. A multistep hierarchical structure-based virtual screening (SBVS) of the 65,375 NCI lead-like compound library led to the identification of two compounds (9 and 28) which noncovalently inhibited the chymotrypsin-like (ChT-L) activity (Ki = 2.18 and 2.12 μM, respectively) with little or no effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and post-glutamyl peptide hydrolase (PGPH) activities. A subsequent hierarchical similarity search over the full NCI database with the most active tripeptide-based inhibitor 9 resulted in the discovery of the β5/β6-specific tripeptide derivative 38 that noncovalently binds the ChT-L site (Ki = 0.42 μM). The solution structure of 9 and 38 was solved by (1)H NMR spectroscopy and the binding mode of the inhibitors was elucidated by docking experiments using the yeast 20S proteasome. Compound 38 (IC50 = 26.7 μM) is slightly more potent than 9 (IC50 = 34.3 μM) at inhibiting survival of dexamethasone-resistant (MM.1R) human multiple myeloma cells. The identified ligand thus provides valuable insights for the future structure-based design of subtype-specific proteasome inhibitors.
- Addresses
- Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
- Autoren
- Carmen Di Giovanni
- Roberta Ettari
- Serena Sarno
- Archimede Rotondo
- Alessandra Bitto
- Francesco Squadrito
- Domenica Altavilla
- Tanja Schirmeister
- Ettore Novellino
- Silvana Grasso
- Maria Zappalà
- Antonio Lavecchia
- DOI
- 10.1016/j.ejmech.2016.05.049
- eISSN
- 1768-3254
- Externe Identifier
- PubMed Identifier: 27318981
- Funding acknowledgements
- Ministero dell’Istruzione, dell’Università̀ e della Ricerca Scientifica e Tecnologica: 2010W7YRLZ_003
- Ministero dell’Istruzione, dell’Università̀ e della Ricerca Scientifica e Tecnologica: 2010W7YRLZ_004
- Ministero dell’Istruzione, dell’Università̀ e della Ricerca Scientifica e Tecnologica: MIUR-PRIN2010-2011
- Open access
- false
- ISSN
- 0223-5234
- Zeitschrift
- European journal of medicinal chemistry
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Proteasome Endopeptidase Complex
- Chymotrypsin
- Drug Evaluation, Preclinical
- Cell Proliferation
- Protein Conformation
- Structure-Activity Relationship
- Substrate Specificity
- User-Computer Interface
- Proteolysis
- Proteasome Inhibitors
- Molecular Docking Simulation
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2016
- Paginierung
- 578 - 591
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Datum der Datenerfassung
- 2016
- Titel
- Identification of noncovalent proteasome inhibitors with high selectivity for chymotrypsin-like activity by a multistep structure-based virtual screening.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 121
Data source: Europe PubMed Central
- Abstract
- Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors, e.g. carfilzomib, used in cancer therapy. A multistep hierarchical structure-based virtual screening (SBVS) of the 65,375 NCI lead-like compound library led to the identification of two compounds (9 and 28) which noncovalently inhibited the chymotrypsin-like (ChT-L) activity (Ki = 2.18 and 2.12 μM, respectively) with little or no effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and post-glutamyl peptide hydrolase (PGPH) activities. A subsequent hierarchical similarity search over the full NCI database with the most active tripeptide-based inhibitor 9 resulted in the discovery of the β5/β6-specific tripeptide derivative 38 that noncovalently binds the ChT-L site (Ki = 0.42 μM). The solution structure of 9 and 38 was solved by (1)H NMR spectroscopy and the binding mode of the inhibitors was elucidated by docking experiments using the yeast 20S proteasome. Compound 38 (IC50 = 26.7 μM) is slightly more potent than 9 (IC50 = 34.3 μM) at inhibiting survival of dexamethasone-resistant (MM.1R) human multiple myeloma cells. The identified ligand thus provides valuable insights for the future structure-based design of subtype-specific proteasome inhibitors.
- Date of acceptance
- 2016
- Autoren
- Carmen Di Giovanni
- Roberta Ettari
- Serena Sarno
- Archimede Rotondo
- Alessandra Bitto
- Francesco Squadrito
- Domenica Altavilla
- Tanja Schirmeister
- Ettore Novellino
- Silvana Grasso
- Maria Zappalà
- Antonio Lavecchia
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/27318981
- DOI
- 10.1016/j.ejmech.2016.05.049
- eISSN
- 1768-3254
- Zeitschrift
- Eur J Med Chem
- Schlüsselwörter
- Docking studies
- Non-covalent
- Peptide scaffold
- Proteasome inhibitors
- Virtual screening
- Cell Line, Tumor
- Cell Proliferation
- Chymotrypsin
- Drug Evaluation, Preclinical
- Humans
- Molecular Docking Simulation
- Proteasome Endopeptidase Complex
- Proteasome Inhibitors
- Protein Conformation
- Proteolysis
- Structure-Activity Relationship
- Substrate Specificity
- User-Computer Interface
- Sprache
- eng
- Country
- France
- Paginierung
- 578 - 591
- PII
- S0223-5234(16)30447-0
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2017
- Titel
- Identification of noncovalent proteasome inhibitors with high selectivity for chymotrypsin-like activity by a multistep structure-based virtual screening.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 121
Data source: PubMed
- Beziehungen:
- Property of