Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> Main Protease
The emergence of SARS-CoV-2, responsible for the global COVID-19 pandemic, requires the rapid development of novel antiviral drugs that would contribute to an effective treatment alongside vaccines. Drug repurposing and development of new molecules targeting numerous viral targets have already led t...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/15/5/539 |
| _version_ | 1827667432133623808 |
|---|---|
| author | Barbara Herlah Andrej Hoivik Luka Jamšek Katja Valjavec Norio Yamamoto Tyuji Hoshino Krištof Kranjc Andrej Perdih |
| author_facet | Barbara Herlah Andrej Hoivik Luka Jamšek Katja Valjavec Norio Yamamoto Tyuji Hoshino Krištof Kranjc Andrej Perdih |
| author_sort | Barbara Herlah |
| collection | DOAJ |
| description | The emergence of SARS-CoV-2, responsible for the global COVID-19 pandemic, requires the rapid development of novel antiviral drugs that would contribute to an effective treatment alongside vaccines. Drug repurposing and development of new molecules targeting numerous viral targets have already led to promising drug candidates. To this end, versatile molecular scaffolds with high functionalization capabilities play a key role. Starting with the clinically used conformationally flexible HIV-1 protease inhibitors that inhibit replication of SARS-CoV-2 and bind major protease 3CL<sup>pro</sup>, we designed and synthesized a series of rigid bicyclo[2.2.2]octenes fused to <i>N</i>-substituted succinimides to test whether this core scaffold could support the development of non-covalent 3CL<sup>pro</sup> inhibitors. Inhibition assays confirmed that some compounds can inhibit the SARS-CoV-2 main protease; the most promising compound <b>11a</b> inhibited 3CL<sup>pro</sup> in micromolar range (IC<sub>50</sub> = 102.2 μM). Molecular simulations of the target-ligand complex in conjunction with dynophore analyses and endpoint free energy calculations provide additional insight and first recommendations for future optimization. The fused bicyclo[2.2.2]octenes can be used as a new potential starting point in the development of non-covalent SARS-CoV-2 3CL<sup>pro</sup> protease inhibitors and the study also substantiates the potential of this versatile scaffold for the development of biologically active molecules. |
| first_indexed | 2024-03-10T03:10:35Z |
| format | Article |
| id | doaj.art-8d0e56a5c12d46d488d1637e278c88c0 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:10:35Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-8d0e56a5c12d46d488d1637e278c88c02023-11-23T12:34:10ZengMDPI AGPharmaceuticals1424-82472022-04-0115553910.3390/ph15050539Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> Main ProteaseBarbara Herlah0Andrej Hoivik1Luka Jamšek2Katja Valjavec3Norio Yamamoto4Tyuji Hoshino5Krištof Kranjc6Andrej Perdih7National Institute of Chemistry, Hajdrihova ulica 19, SI-1000 Ljubljana, SloveniaFaculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, SloveniaFaculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova ulica 19, SI-1000 Ljubljana, SloveniaDepartment of Microbiology, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Kanagawa, JapanGraduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Chiba, JapanFaculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova ulica 19, SI-1000 Ljubljana, SloveniaThe emergence of SARS-CoV-2, responsible for the global COVID-19 pandemic, requires the rapid development of novel antiviral drugs that would contribute to an effective treatment alongside vaccines. Drug repurposing and development of new molecules targeting numerous viral targets have already led to promising drug candidates. To this end, versatile molecular scaffolds with high functionalization capabilities play a key role. Starting with the clinically used conformationally flexible HIV-1 protease inhibitors that inhibit replication of SARS-CoV-2 and bind major protease 3CL<sup>pro</sup>, we designed and synthesized a series of rigid bicyclo[2.2.2]octenes fused to <i>N</i>-substituted succinimides to test whether this core scaffold could support the development of non-covalent 3CL<sup>pro</sup> inhibitors. Inhibition assays confirmed that some compounds can inhibit the SARS-CoV-2 main protease; the most promising compound <b>11a</b> inhibited 3CL<sup>pro</sup> in micromolar range (IC<sub>50</sub> = 102.2 μM). Molecular simulations of the target-ligand complex in conjunction with dynophore analyses and endpoint free energy calculations provide additional insight and first recommendations for future optimization. The fused bicyclo[2.2.2]octenes can be used as a new potential starting point in the development of non-covalent SARS-CoV-2 3CL<sup>pro</sup> protease inhibitors and the study also substantiates the potential of this versatile scaffold for the development of biologically active molecules.https://www.mdpi.com/1424-8247/15/5/539bicyclo[2.2.2]octenesmolecular scaffoldsSARS-CoV-23CL<sup>pro</sup> main proteaseCOVID-19 antiviral drugs |
| spellingShingle | Barbara Herlah Andrej Hoivik Luka Jamšek Katja Valjavec Norio Yamamoto Tyuji Hoshino Krištof Kranjc Andrej Perdih Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> Main Protease Pharmaceuticals bicyclo[2.2.2]octenes molecular scaffolds SARS-CoV-2 3CL<sup>pro</sup> main protease COVID-19 antiviral drugs |
| title | Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> Main Protease |
| title_full | Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> Main Protease |
| title_fullStr | Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> Main Protease |
| title_full_unstemmed | Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> Main Protease |
| title_short | Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> Main Protease |
| title_sort | design synthesis and evaluation of fused bicyclo 2 2 2 octene as a potential core scaffold for the non covalent inhibitors of sars cov 2 3cl sup pro sup main protease |
| topic | bicyclo[2.2.2]octenes molecular scaffolds SARS-CoV-2 3CL<sup>pro</sup> main protease COVID-19 antiviral drugs |
| url | https://www.mdpi.com/1424-8247/15/5/539 |
| work_keys_str_mv | AT barbaraherlah designsynthesisandevaluationoffusedbicyclo222octeneasapotentialcorescaffoldforthenoncovalentinhibitorsofsarscov23clsupprosupmainprotease AT andrejhoivik designsynthesisandevaluationoffusedbicyclo222octeneasapotentialcorescaffoldforthenoncovalentinhibitorsofsarscov23clsupprosupmainprotease AT lukajamsek designsynthesisandevaluationoffusedbicyclo222octeneasapotentialcorescaffoldforthenoncovalentinhibitorsofsarscov23clsupprosupmainprotease AT katjavaljavec designsynthesisandevaluationoffusedbicyclo222octeneasapotentialcorescaffoldforthenoncovalentinhibitorsofsarscov23clsupprosupmainprotease AT norioyamamoto designsynthesisandevaluationoffusedbicyclo222octeneasapotentialcorescaffoldforthenoncovalentinhibitorsofsarscov23clsupprosupmainprotease AT tyujihoshino designsynthesisandevaluationoffusedbicyclo222octeneasapotentialcorescaffoldforthenoncovalentinhibitorsofsarscov23clsupprosupmainprotease AT kristofkranjc designsynthesisandevaluationoffusedbicyclo222octeneasapotentialcorescaffoldforthenoncovalentinhibitorsofsarscov23clsupprosupmainprotease AT andrejperdih designsynthesisandevaluationoffusedbicyclo222octeneasapotentialcorescaffoldforthenoncovalentinhibitorsofsarscov23clsupprosupmainprotease |