New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies
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 s...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/8/1096 |
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| author | Romina A. Guedes Jorge H. Grilo Andreia N. Carvalho Pedro M. P. Fernandes Ana S. Ressurreição Vanessa Brito Adriana O. Santos Samuel Silvestre Eleonora Gallerani Maria João Gama Riccardo Gavioli Jorge A. R. Salvador Rita C. Guedes |
| author_facet | Romina A. Guedes Jorge H. Grilo Andreia N. Carvalho Pedro M. P. Fernandes Ana S. Ressurreição Vanessa Brito Adriana O. Santos Samuel Silvestre Eleonora Gallerani Maria João Gama Riccardo Gavioli Jorge A. R. Salvador Rita C. Guedes |
| author_sort | Romina A. Guedes |
| collection | DOAJ |
| description | 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 <b>4</b> (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 IC<sub>50</sub> values in the low micromolar range). Molecular docking studies revealed that compound <b>4</b> 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. |
| first_indexed | 2024-03-10T23:39:50Z |
| format | Article |
| id | doaj.art-b023cf597f664b0180e81c7abc9a0029 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T23:39:50Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-b023cf597f664b0180e81c7abc9a00292023-11-19T02:33:50ZengMDPI AGPharmaceuticals1424-82472023-08-01168109610.3390/ph16081096New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro MethodologiesRomina A. Guedes0Jorge H. Grilo1Andreia N. Carvalho2Pedro M. P. Fernandes3Ana S. Ressurreição4Vanessa Brito5Adriana O. Santos6Samuel Silvestre7Eleonora Gallerani8Maria João Gama9Riccardo Gavioli10Jorge A. R. Salvador11Rita C. Guedes12Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, PortugalHealth Sciences Research Centre (CICS-UBI), University of Beira Interior, 6200-506 Covilhã, PortugalHealth Sciences Research Centre (CICS-UBI), University of Beira Interior, 6200-506 Covilhã, PortugalHealth Sciences Research Centre (CICS-UBI), University of Beira Interior, 6200-506 Covilhã, PortugalDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, ItalyResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, PortugalDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, ItalyCenter for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, PortugalCancer 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 <b>4</b> (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 IC<sub>50</sub> values in the low micromolar range). Molecular docking studies revealed that compound <b>4</b> 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.https://www.mdpi.com/1424-8247/16/8/1096ubiquitin–proteasome systemproteasomeproteasome inhibitorscancerleukemialymphoma |
| spellingShingle | Romina A. Guedes Jorge H. Grilo Andreia N. Carvalho Pedro M. P. Fernandes Ana S. Ressurreição Vanessa Brito Adriana O. Santos Samuel Silvestre Eleonora Gallerani Maria João Gama Riccardo Gavioli Jorge A. R. Salvador Rita C. Guedes New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies Pharmaceuticals ubiquitin–proteasome system proteasome proteasome inhibitors cancer leukemia lymphoma |
| title | New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies |
| title_full | New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies |
| title_fullStr | New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies |
| title_full_unstemmed | New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies |
| title_short | New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies |
| title_sort | new scaffolds of proteasome inhibitors boosting anticancer potential by exploiting the synergy of in silico and in vitro methodologies |
| topic | ubiquitin–proteasome system proteasome proteasome inhibitors cancer leukemia lymphoma |
| url | https://www.mdpi.com/1424-8247/16/8/1096 |
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