Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment
Abstract In the current study we suggest a novel approach to curb non-alcoholic steatohepatitis (NASH) progression, and we suggest privileged scaffolds for the design of novel compounds for this aim. NASH is an advanced form of non-alcoholic fatty liver disease that can further progress into fibrosi...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | BMC Chemistry |
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| Online Access: | https://doi.org/10.1186/s13065-023-01081-3 |
| _version_ | 1797363674420084736 |
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| author | Yara A. Zaky Mai W. Rashad Marwa A. Zaater Ahmed M. El Kerdawy |
| author_facet | Yara A. Zaky Mai W. Rashad Marwa A. Zaater Ahmed M. El Kerdawy |
| author_sort | Yara A. Zaky |
| collection | DOAJ |
| description | Abstract In the current study we suggest a novel approach to curb non-alcoholic steatohepatitis (NASH) progression, and we suggest privileged scaffolds for the design of novel compounds for this aim. NASH is an advanced form of non-alcoholic fatty liver disease that can further progress into fibrosis, cirrhosis, and hepatocellular carcinoma. It is a widely emerging disease affecting 25% of the global population and has no current approved treatments. Protein kinases are key regulators of cellular pathways, of which, Rho-associated protein kinase 1 (ROCK1) and apoptosis signal–regulating kinase 1 (ASK1) play an important role in the progression of NASH and they stand out as promising targets for NASH therapy. Interestingly, their kinase domains are found to be similar in sequence and topology; therefore, dual inhibition of ROCK1 and ASK1 is expected to be amenable and could achieve a more favourable outcome. To reach this goal, a training set of ROCK1 and ASK1 protein structures co-crystalized with type 1 (ATP-competitive) inhibitors was constructed to manually generate receptor-based pharmacophore models representing ROCK1 and ASK1 inhibitors’ common pharmacophoric features. The models produced were assessed using a test set of both ROCK1 and ASK1 actives and decoys, and their performance was evaluated using different assessment metrics. The best pharmacophore model obtained, showing a Mathew’s correlation coefficient (MCC) of 0.71, was then used to screen the ZINC purchasable database retrieving 6178 hits that were filtered accordingly using several medicinal chemistry and pharmacokinetics filters returning 407 promising compounds. To confirm that these compounds are capable of binding to the target kinases, they were subjected to molecular docking simulations at both protein structures. The results were then assessed individually and filtered, setting the spotlight on various privileged scaffolds that could be exploited as the nucleus for designing novel ROCK1/ASK1 dual inhibitors. |
| first_indexed | 2024-03-08T16:24:22Z |
| format | Article |
| id | doaj.art-82e08e6c83ee4375ab8dbf2e4eb6e07b |
| institution | Directory Open Access Journal |
| issn | 2661-801X |
| language | English |
| last_indexed | 2024-03-08T16:24:22Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Chemistry |
| spelling | doaj.art-82e08e6c83ee4375ab8dbf2e4eb6e07b2024-01-07T12:07:00ZengBMCBMC Chemistry2661-801X2024-01-0118112810.1186/s13065-023-01081-3Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatmentYara A. Zaky0Mai W. Rashad1Marwa A. Zaater2Ahmed M. El Kerdawy3Department of Chemistry, School of Pharmacy, Newgiza University (NGU)Department of Chemistry, School of Pharmacy, Newgiza University (NGU)Master Postgraduate Program, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo UniversityDepartment of Chemistry, School of Pharmacy, Newgiza University (NGU)Abstract In the current study we suggest a novel approach to curb non-alcoholic steatohepatitis (NASH) progression, and we suggest privileged scaffolds for the design of novel compounds for this aim. NASH is an advanced form of non-alcoholic fatty liver disease that can further progress into fibrosis, cirrhosis, and hepatocellular carcinoma. It is a widely emerging disease affecting 25% of the global population and has no current approved treatments. Protein kinases are key regulators of cellular pathways, of which, Rho-associated protein kinase 1 (ROCK1) and apoptosis signal–regulating kinase 1 (ASK1) play an important role in the progression of NASH and they stand out as promising targets for NASH therapy. Interestingly, their kinase domains are found to be similar in sequence and topology; therefore, dual inhibition of ROCK1 and ASK1 is expected to be amenable and could achieve a more favourable outcome. To reach this goal, a training set of ROCK1 and ASK1 protein structures co-crystalized with type 1 (ATP-competitive) inhibitors was constructed to manually generate receptor-based pharmacophore models representing ROCK1 and ASK1 inhibitors’ common pharmacophoric features. The models produced were assessed using a test set of both ROCK1 and ASK1 actives and decoys, and their performance was evaluated using different assessment metrics. The best pharmacophore model obtained, showing a Mathew’s correlation coefficient (MCC) of 0.71, was then used to screen the ZINC purchasable database retrieving 6178 hits that were filtered accordingly using several medicinal chemistry and pharmacokinetics filters returning 407 promising compounds. To confirm that these compounds are capable of binding to the target kinases, they were subjected to molecular docking simulations at both protein structures. The results were then assessed individually and filtered, setting the spotlight on various privileged scaffolds that could be exploited as the nucleus for designing novel ROCK1/ASK1 dual inhibitors.https://doi.org/10.1186/s13065-023-01081-3NASHASK1MAP3K5ROCK1Pharmacophore modelingMolecular docking |
| spellingShingle | Yara A. Zaky Mai W. Rashad Marwa A. Zaater Ahmed M. El Kerdawy Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment BMC Chemistry NASH ASK1 MAP3K5 ROCK1 Pharmacophore modeling Molecular docking |
| title | Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment |
| title_full | Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment |
| title_fullStr | Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment |
| title_full_unstemmed | Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment |
| title_short | Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment |
| title_sort | discovery of dual rho associated protein kinase 1 rock1 apoptosis signal regulating kinase 1 ask1 inhibitors as a novel approach for non alcoholic steatohepatitis nash treatment |
| topic | NASH ASK1 MAP3K5 ROCK1 Pharmacophore modeling Molecular docking |
| url | https://doi.org/10.1186/s13065-023-01081-3 |
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