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Title: New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies
Authors: Guedes, Romina A. 
Grilo, Jorge H.
Carvalho, Andreia N.
Fernandes, Pedro M. P. 
Ressurreição, Ana S.
Brito, Vanessa 
Santos, Adriana O.
Silvestre, Samuel 
Gallerani, Eleonora
Gama, Maria João
Gavioli, Riccardo
Salvador, Jorge A. R. 
Guedes, Rita C.
Keywords: ubiquitin–proteasome system; proteasome; proteasome inhibitors; cancer; leukemia; lymphoma; multiple myeloma; molecular docking; virtual screening
Issue Date: 2-Aug-2023
Publisher: MDPI
Project: This research was funded by FCT—Fundação para a Ciência e a Tecnologia, thorough the grants PTDC/QEQ-MED/7042/2014, UID/DTP/04138/2019 and the PhD grant SFRH/BD/104441/2014 (R.A.G.) and was also supported by the European Structural & Investment Funds through the COMPETE Programme under grant LISBOA-01-0145-FEDER-016405 (SAICTPAC/0019/2015). J.A.R.S. is also thankful for the funding from the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under the projects CENTRO-01-0247-FEDER-003269 (Drugs2CAD) and CENTRO-01-0145-FEDER-000012 (HealthyAging2020) and through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization. 
Serial title, monograph or event: Pharmaceuticals
Volume: 16
Issue: 8
Abstract: Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin-proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC50 values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign.
ISSN: 1424-8247
DOI: 10.3390/ph16081096
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FFUC- Artigos em Revistas Internacionais
I&D CIBB - Artigos em Revistas Internacionais

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