Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study
Abstract A serine protease called prolyl endopeptidase (PEP) hydrolyses the peptide bonds on the carboxy side of the proline ring. The excessive PEP expression in brain results in neurodegenerative illnesses like dementia, Alzheimer’s disease, and Parkinson's disease. Results of the prior studi...
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Nature Portfolio
2024-04-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-58428-6 |
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| author | Saeed Ullah Farheen Mansoor Salman Ali Khan Uzma Jabeen Amany I. Almars Hailah M. Almohaimeed Ahmed M. Basri Fahad M. Alshabrmi |
| author_facet | Saeed Ullah Farheen Mansoor Salman Ali Khan Uzma Jabeen Amany I. Almars Hailah M. Almohaimeed Ahmed M. Basri Fahad M. Alshabrmi |
| author_sort | Saeed Ullah |
| collection | DOAJ |
| description | Abstract A serine protease called prolyl endopeptidase (PEP) hydrolyses the peptide bonds on the carboxy side of the proline ring. The excessive PEP expression in brain results in neurodegenerative illnesses like dementia, Alzheimer’s disease, and Parkinson's disease. Results of the prior studies on antioxidant activity, and the non-cytotoxic effect of bi-carbazole-linked triazoles, encouraged us to extend our studies towards its anti-diabetic potential. Hence, for this purpose all compounds 1–9 were evaluated to reveal their anti-prolyl endo peptidase activity. Fortunately, seven compounds resulted into significant inhibitory capability ranging from 26 to 63 µM. Among them six compounds 4–9 exhibited more potent inhibitory activity with IC50 values 46.10 ± 1.16, 42.30 ± 1.18, 37.14 ± 1.21, 26.29 ± 0.76, 28.31 ± 0.64 and 31.11 ± 0.84 µM respectively, while compound 3 was the least active compound in the series with IC50 value 63.10 ± 1.58 µM comparing with standard PEP inhibitor bacitracin (IC50 = 125 ± 1.50 µM). Moreover, mechanistic study was performed for the most active compounds 7 and 8 with K i values 24.10 ± 0.0076 and 23.67 ± 0.0084 µM respectively. Further, the in silico studies suggested that the compounds exhibited potential interactions and significant molecular conformations, thereby elucidating the structural basis for their inhibitory effects. |
| first_indexed | 2024-04-24T12:40:01Z |
| format | Article |
| id | doaj.art-fdb860b5a0a148bbbec8cb3c2e7e7651 |
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| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T12:40:01Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-fdb860b5a0a148bbbec8cb3c2e7e76512024-04-07T11:18:59ZengNature PortfolioScientific Reports2045-23222024-04-0114111310.1038/s41598-024-58428-6Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico studySaeed Ullah0Farheen Mansoor1Salman Ali Khan2Uzma Jabeen3Amany I. Almars4Hailah M. Almohaimeed5Ahmed M. Basri6Fahad M. Alshabrmi7Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of KarachiDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of KarachiTunneling Group, Biotechnology Centre, Doctoral School, Silesian University of TechnologyDepartment of Biochemistry, Federal Urdu University of KarachiDepartment of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz UniversityDepartment of Basic Science, College of Medicine, Princess Nourah Bint Abdulrahman UniversityDepartment of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz UniversityDepartment of Medical Laboratories, College of Applied Medical Sciences, Qassim UniversityAbstract A serine protease called prolyl endopeptidase (PEP) hydrolyses the peptide bonds on the carboxy side of the proline ring. The excessive PEP expression in brain results in neurodegenerative illnesses like dementia, Alzheimer’s disease, and Parkinson's disease. Results of the prior studies on antioxidant activity, and the non-cytotoxic effect of bi-carbazole-linked triazoles, encouraged us to extend our studies towards its anti-diabetic potential. Hence, for this purpose all compounds 1–9 were evaluated to reveal their anti-prolyl endo peptidase activity. Fortunately, seven compounds resulted into significant inhibitory capability ranging from 26 to 63 µM. Among them six compounds 4–9 exhibited more potent inhibitory activity with IC50 values 46.10 ± 1.16, 42.30 ± 1.18, 37.14 ± 1.21, 26.29 ± 0.76, 28.31 ± 0.64 and 31.11 ± 0.84 µM respectively, while compound 3 was the least active compound in the series with IC50 value 63.10 ± 1.58 µM comparing with standard PEP inhibitor bacitracin (IC50 = 125 ± 1.50 µM). Moreover, mechanistic study was performed for the most active compounds 7 and 8 with K i values 24.10 ± 0.0076 and 23.67 ± 0.0084 µM respectively. Further, the in silico studies suggested that the compounds exhibited potential interactions and significant molecular conformations, thereby elucidating the structural basis for their inhibitory effects.https://doi.org/10.1038/s41598-024-58428-6Bi-carbazole-linked triazolesIn vitroMolecular docking simulationProlyl endo peptidase inhibitory activityKinetic studies |
| spellingShingle | Saeed Ullah Farheen Mansoor Salman Ali Khan Uzma Jabeen Amany I. Almars Hailah M. Almohaimeed Ahmed M. Basri Fahad M. Alshabrmi Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study Scientific Reports Bi-carbazole-linked triazoles In vitro Molecular docking simulation Prolyl endo peptidase inhibitory activity Kinetic studies |
| title | Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study |
| title_full | Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study |
| title_fullStr | Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study |
| title_full_unstemmed | Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study |
| title_short | Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study |
| title_sort | exploring bi carbazole linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study |
| topic | Bi-carbazole-linked triazoles In vitro Molecular docking simulation Prolyl endo peptidase inhibitory activity Kinetic studies |
| url | https://doi.org/10.1038/s41598-024-58428-6 |
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