Discovery of the bacterial HslV protease activators as lead molecules with novel mode of action
The HslVU enzyme complex, a proteasomal analog found in bacteria, consists of two components, i.e., the HslV protease and the HslU ATPase. These proteins come together to form a functional enzyme complex, where the C-terminal helix of each HslU subunit is inserted into the binding pocket of each Hsl...
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| Format: | Article |
| Language: | English |
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De Gruyter
2025-02-01
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| Series: | Open Chemistry |
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| Online Access: | https://doi.org/10.1515/chem-2024-0127 |
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| author | Aurangzeb Sana Aurongzeb Muhammad Shamim Shahbaz Rashid Yasmeen Khan Khalid Mohammed Aziz Tariq Alharbi Metab Alasmari Abdullah F. |
| author_facet | Aurangzeb Sana Aurongzeb Muhammad Shamim Shahbaz Rashid Yasmeen Khan Khalid Mohammed Aziz Tariq Alharbi Metab Alasmari Abdullah F. |
| author_sort | Aurangzeb Sana |
| collection | DOAJ |
| description | The HslVU enzyme complex, a proteasomal analog found in bacteria, consists of two components, i.e., the HslV protease and the HslU ATPase. These proteins come together to form a functional enzyme complex, where the C-terminal helix of each HslU subunit is inserted into the binding pocket of each HslV dimer. This interaction leads to the activation of the HslV protease through allosteric mechanisms, enabling its enzymatic function. This bacterial complex is reflected as an attractive target for drug development due to its presence in disease-causing microorganisms and concurrent absence in humans. The objective of this research was to identify certain promising drug candidates that could excessively stimulate the HslV protease, leading to uncontrolled protein breakdown in the pathogens. Four dihydropyrimidone derivatives have been identified as potential activators of HslV protease exhibiting high docking scores, favorable binding patterns, and significant in vitro activation capabilities. These compounds have demonstrated effective dose 50 values within the sub-micromolar range, i.e., 0.4–0.58 µM. Normal mode analysis investigations provided additional confirmation regarding the stability of the conformational interactions between the HslV protease and the active compounds. In addition, the predicted absorption, distribution, metabolism, excretion, and toxicity properties of these lead compounds remarkably demonstrated their considerable drug-like and non-toxic qualities. This study not only presents more potent small non-peptide activators of the HslV protease but also enhances the understanding regarding the mechanism of HslVU complex activation via small non-peptidic molecules. |
| format | Article |
| id | doaj-art-a121eb637a35432796f1eeee5a95a0e0 |
| institution | Kabale University |
| issn | 2391-5420 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | De Gruyter |
| record_format | Article |
| series | Open Chemistry |
| spelling | doaj-art-a121eb637a35432796f1eeee5a95a0e02025-02-10T13:24:13ZengDe GruyterOpen Chemistry2391-54202025-02-01231689990910.1515/chem-2024-0127Discovery of the bacterial HslV protease activators as lead molecules with novel mode of actionAurangzeb Sana0Aurongzeb Muhammad1Shamim Shahbaz2Rashid Yasmeen3Khan Khalid Mohammed4Aziz Tariq5Alharbi Metab6Alasmari Abdullah F.7Department of Biochemistry, University of Karachi, Karachi, 75270, PakistanDepartment of Biotechnology, Faculty of Engineering Sciences & Technology, Hamdard University, Karachi74600, PakistanH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, PakistanDepartment of Biochemistry, University of Karachi, Karachi, 75270, PakistanH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, PakistanDepartment of Agriculture, University of Ioannina, Arta, 47100, GreeceDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi ArabiaThe HslVU enzyme complex, a proteasomal analog found in bacteria, consists of two components, i.e., the HslV protease and the HslU ATPase. These proteins come together to form a functional enzyme complex, where the C-terminal helix of each HslU subunit is inserted into the binding pocket of each HslV dimer. This interaction leads to the activation of the HslV protease through allosteric mechanisms, enabling its enzymatic function. This bacterial complex is reflected as an attractive target for drug development due to its presence in disease-causing microorganisms and concurrent absence in humans. The objective of this research was to identify certain promising drug candidates that could excessively stimulate the HslV protease, leading to uncontrolled protein breakdown in the pathogens. Four dihydropyrimidone derivatives have been identified as potential activators of HslV protease exhibiting high docking scores, favorable binding patterns, and significant in vitro activation capabilities. These compounds have demonstrated effective dose 50 values within the sub-micromolar range, i.e., 0.4–0.58 µM. Normal mode analysis investigations provided additional confirmation regarding the stability of the conformational interactions between the HslV protease and the active compounds. In addition, the predicted absorption, distribution, metabolism, excretion, and toxicity properties of these lead compounds remarkably demonstrated their considerable drug-like and non-toxic qualities. This study not only presents more potent small non-peptide activators of the HslV protease but also enhances the understanding regarding the mechanism of HslVU complex activation via small non-peptidic molecules.https://doi.org/10.1515/chem-2024-0127the hslvu complexhslv protease activatorsstructural bioinformaticsnma analysismolecular docking studies |
| spellingShingle | Aurangzeb Sana Aurongzeb Muhammad Shamim Shahbaz Rashid Yasmeen Khan Khalid Mohammed Aziz Tariq Alharbi Metab Alasmari Abdullah F. Discovery of the bacterial HslV protease activators as lead molecules with novel mode of action Open Chemistry the hslvu complex hslv protease activators structural bioinformatics nma analysis molecular docking studies |
| title | Discovery of the bacterial HslV protease activators as lead molecules with novel mode of action |
| title_full | Discovery of the bacterial HslV protease activators as lead molecules with novel mode of action |
| title_fullStr | Discovery of the bacterial HslV protease activators as lead molecules with novel mode of action |
| title_full_unstemmed | Discovery of the bacterial HslV protease activators as lead molecules with novel mode of action |
| title_short | Discovery of the bacterial HslV protease activators as lead molecules with novel mode of action |
| title_sort | discovery of the bacterial hslv protease activators as lead molecules with novel mode of action |
| topic | the hslvu complex hslv protease activators structural bioinformatics nma analysis molecular docking studies |
| url | https://doi.org/10.1515/chem-2024-0127 |
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