In Silico Profiling of Histone Deacetylase 8 Inhibitory Activity: A Computational Analysis of Novel Dipeptide-Based Compounds Cross-Linked with Hydroxamic Acid
This study involved the development of innovative compounds consisting of dipeptide cross-links combined with hydroxamic acid. Our objective was to assess their binding affinities with histone deacetylase 8 (HDAC8) by conducting a docking study, comparing the results with the reference ligand, sube...
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| Format: | Article |
| Language: | English |
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College of Pharmacy / Mustansiriyah University
2024-04-01
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| Series: | Al-Mustansiriyah Journal of Pharmaceutical Sciences |
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| Online Access: | https://ajps.uomustansiriyah.edu.iq/index.php/AJPS/article/view/1059 |
| _version_ | 1797219180361023488 |
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| author | omer mohammed ammash Shakir M. Alwan Ali R.M. albakaa İsmail Alshrif Ibrheam ben Sulaiman |
| author_facet | omer mohammed ammash Shakir M. Alwan Ali R.M. albakaa İsmail Alshrif Ibrheam ben Sulaiman |
| author_sort | omer mohammed ammash |
| collection | DOAJ |
| description |
This study involved the development of innovative compounds consisting of dipeptide cross-links combined with hydroxamic acid. Our objective was to assess their binding affinities with histone deacetylase 8 (HDAC8) by conducting a docking study, comparing the results with the reference ligand, suberoylanilide hydroxamic acid (SAHA).
Docking scores were measured in terms of ΔG (Kcal/mol), and the recorded scores for compounds 2A-D were found to be higher than that of SAHA, with values of 87.36, 80.46, 79.42, and 74.14, respectively. Notably, compound 2A, a dipeptide consisting of L-tryptophyl-L-tyrosine linked to a hydroxamic acid moiety, exhibited the highest docking score of 87.36. This finding suggests that compound 2A may possess the most potent HDAC8 inhibitory activity among the other designed compounds. Furthermore, we utilized the SwissADME server to predict the physicochemical properties and additional ADME parameters for the designed compounds. The analysis revealed that all investigated compounds exhibited a high potential for passive oral absorption and demonstrated no penetration into the blood-brain barrier. Compound 2A, 2B, and 2D exhibited one Lipinski's rule violation each, whereas Compound 2C demonstrated no such violations in all parameters. Additionally, compounds 2A and 2C exhibited potential as P-glycoprotein (P-gp) substrates. SAHA did not exhibit inhibition of any of the cytochrome P450 (CYP) enzymes used in this study, whereas compounds 2B, 2C and 2D displayed possible inhibitory activities. These compelling findings provide encouraging prospects for the future synthesis of the designed compounds and warrant further evaluation through in vitro and in vivo biological studies.
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| first_indexed | 2024-04-24T12:29:33Z |
| format | Article |
| id | doaj.art-533227a841d44413be19c7f280b35531 |
| institution | Directory Open Access Journal |
| issn | 1815-0993 2959-183X |
| language | English |
| last_indexed | 2024-04-24T12:29:33Z |
| publishDate | 2024-04-01 |
| publisher | College of Pharmacy / Mustansiriyah University |
| record_format | Article |
| series | Al-Mustansiriyah Journal of Pharmaceutical Sciences |
| spelling | doaj.art-533227a841d44413be19c7f280b355312024-04-08T06:58:17ZengCollege of Pharmacy / Mustansiriyah UniversityAl-Mustansiriyah Journal of Pharmaceutical Sciences1815-09932959-183X2024-04-0124210.32947/ajps.v24i2.1059In Silico Profiling of Histone Deacetylase 8 Inhibitory Activity: A Computational Analysis of Novel Dipeptide-Based Compounds Cross-Linked with Hydroxamic Acidomer mohammed ammash0Shakir M. Alwan1Ali R.M. albakaa 2İsmail Alshrif Ibrheam ben Sulaiman3chemistry departmentDepartment of Pharmacy, Al-Farabi University CollegeDepartment of Pharmaceutical Chemistry, College of Pharmacy/Al-Mustansiriyah Universityjanzour Department of Pharmacy, College of Education, University of Tripoli This study involved the development of innovative compounds consisting of dipeptide cross-links combined with hydroxamic acid. Our objective was to assess their binding affinities with histone deacetylase 8 (HDAC8) by conducting a docking study, comparing the results with the reference ligand, suberoylanilide hydroxamic acid (SAHA). Docking scores were measured in terms of ΔG (Kcal/mol), and the recorded scores for compounds 2A-D were found to be higher than that of SAHA, with values of 87.36, 80.46, 79.42, and 74.14, respectively. Notably, compound 2A, a dipeptide consisting of L-tryptophyl-L-tyrosine linked to a hydroxamic acid moiety, exhibited the highest docking score of 87.36. This finding suggests that compound 2A may possess the most potent HDAC8 inhibitory activity among the other designed compounds. Furthermore, we utilized the SwissADME server to predict the physicochemical properties and additional ADME parameters for the designed compounds. The analysis revealed that all investigated compounds exhibited a high potential for passive oral absorption and demonstrated no penetration into the blood-brain barrier. Compound 2A, 2B, and 2D exhibited one Lipinski's rule violation each, whereas Compound 2C demonstrated no such violations in all parameters. Additionally, compounds 2A and 2C exhibited potential as P-glycoprotein (P-gp) substrates. SAHA did not exhibit inhibition of any of the cytochrome P450 (CYP) enzymes used in this study, whereas compounds 2B, 2C and 2D displayed possible inhibitory activities. These compelling findings provide encouraging prospects for the future synthesis of the designed compounds and warrant further evaluation through in vitro and in vivo biological studies. https://ajps.uomustansiriyah.edu.iq/index.php/AJPS/article/view/1059Dipeptide cross-linksHydroxamic acidHistone deacetylase 8 (HDAC8)Binding affinitiesDocking studyPhysicochemical properties |
| spellingShingle | omer mohammed ammash Shakir M. Alwan Ali R.M. albakaa İsmail Alshrif Ibrheam ben Sulaiman In Silico Profiling of Histone Deacetylase 8 Inhibitory Activity: A Computational Analysis of Novel Dipeptide-Based Compounds Cross-Linked with Hydroxamic Acid Al-Mustansiriyah Journal of Pharmaceutical Sciences Dipeptide cross-links Hydroxamic acid Histone deacetylase 8 (HDAC8) Binding affinities Docking study Physicochemical properties |
| title | In Silico Profiling of Histone Deacetylase 8 Inhibitory Activity: A Computational Analysis of Novel Dipeptide-Based Compounds Cross-Linked with Hydroxamic Acid |
| title_full | In Silico Profiling of Histone Deacetylase 8 Inhibitory Activity: A Computational Analysis of Novel Dipeptide-Based Compounds Cross-Linked with Hydroxamic Acid |
| title_fullStr | In Silico Profiling of Histone Deacetylase 8 Inhibitory Activity: A Computational Analysis of Novel Dipeptide-Based Compounds Cross-Linked with Hydroxamic Acid |
| title_full_unstemmed | In Silico Profiling of Histone Deacetylase 8 Inhibitory Activity: A Computational Analysis of Novel Dipeptide-Based Compounds Cross-Linked with Hydroxamic Acid |
| title_short | In Silico Profiling of Histone Deacetylase 8 Inhibitory Activity: A Computational Analysis of Novel Dipeptide-Based Compounds Cross-Linked with Hydroxamic Acid |
| title_sort | in silico profiling of histone deacetylase 8 inhibitory activity a computational analysis of novel dipeptide based compounds cross linked with hydroxamic acid |
| topic | Dipeptide cross-links Hydroxamic acid Histone deacetylase 8 (HDAC8) Binding affinities Docking study Physicochemical properties |
| url | https://ajps.uomustansiriyah.edu.iq/index.php/AJPS/article/view/1059 |
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