Improved Inhibitory and Absorption, Distribution, Metabolism, Excretion, and Toxicology (ADMET) Properties of Blebbistatin Derivatives Indicate That Blebbistatin Scaffold Is Ideal for drug Development Targeting Myosin-2
| Autor: | Zsolt Borhegyi, Kinga Oravecz, László Kornya, Sharad Kumar Suthar, Ádám Kiss, Máté Déri, Suman Nag, Jacob L. Krans, Katalin Monostory, Máté Gyimesi, Kamirán Á. Hamow, András Málnási-Csizmadia, Ivan Tomasic, István Lőrincz, Patrick J. Tierney, Anna Á. Rauscher, Mihály Kovács, Pál Szabó |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Gene isoform Drug Scaffold Protein Conformation media_common.quotation_subject Molecular Dynamics Simulation Myosins Inhibitory postsynaptic potential Heterocyclic Compounds 4 or More Rings 03 medical and health sciences 0302 clinical medicine Drug Discovery Myosin Animals Humans Distribution (pharmacology) Tissue Distribution media_common Pharmacology Chemistry Metabolism Rats Cell biology 030104 developmental biology Absorption Physicochemical Drug development Molecular Medicine 030217 neurology & neurosurgery |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 376:358-373 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Blebbistatin, para-nitroblebbistatin (NBleb), and para-aminoblebbistatin (AmBleb) are highly useful tool compounds as they selectively inhibit the ATPase activity of myosin-2 family proteins. Despite the medical importance of the myosin-2 family as drug targets, chemical optimization has not yet provided a promising lead for drug development because previous structure-activity-relationship studies were limited to a single myosin-2 isoform. Here we evaluated the potential of blebbistatin scaffold for drug development and found that D-ring substitutions can fine-tune isoform specificity, absorption-distribution-metabolism-excretion, and toxicological properties. We defined the inhibitory properties of NBleb and AmBleb on seven different myosin-2 isoforms, which revealed an unexpected potential for isoform specific inhibition. We also found that NBleb metabolizes six times slower than blebbistatin and AmBleb in rats, whereas AmBleb metabolizes two times slower than blebbistatin and NBleb in human, and that AmBleb accumulates in muscle tissues. Moreover, mutagenicity was also greatly reduced in case of AmBleb. These results demonstrate that small substitutions have beneficial functional and pharmacological consequences, which highlight the potential of the blebbistatin scaffold for drug development targeting myosin-2 family proteins and delineate a route for defining the chemical properties of further derivatives to be developed. SIGNIFICANCE STATEMENT Small substitutions on the blebbistatin scaffold have beneficial functional and pharmacological consequences, highlighting their potential in drug development targeting myosin-2 family proteins. |
| Databáze: | OpenAIRE |
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