Identification of noncovalent proteasome inhibitors with high selectivity for chymotrypsin-like activity by a multistep structure based virtual screening

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

Datenquelle: 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

Datenquelle: 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

Datenquelle: PubMed

Identification of noncovalent proteasome inhibitors with high selectivity for chymotrypsin-like activity by a multistep structure based virtual screening

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