Integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma-linked inflammatory and haematological malignancies
Elevated levels of haptoglobin are commonly observed in conditions characterised by an increased erythrocyte sedimentation rate which are acute-phase reactants. These conditions include infection, trauma, inflammation, hepatitis, amyloidosis, collagen diseases, lymphoma, leukaemia, as well as obstru...
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Frontiers Media S.A.
2025-06-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2025.1611972/full |
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| author | Abdulaziz H. Al Khzem Shaban Ahmad |
| author_facet | Abdulaziz H. Al Khzem Shaban Ahmad |
| author_sort | Abdulaziz H. Al Khzem |
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| description | Elevated levels of haptoglobin are commonly observed in conditions characterised by an increased erythrocyte sedimentation rate which are acute-phase reactants. These conditions include infection, trauma, inflammation, hepatitis, amyloidosis, collagen diseases, lymphoma, leukaemia, as well as obstructive and biliary diseases. However, no significant drugs are currently available to manage these conditions, making therapeutic intervention crucial effectively. In this study, we performed an extensive screening of the DrugBank database against the human haptoglobin protein (PDB ID: 4X0L) using High-Throughput Virtual Screening (HTVS), Standard Precision and Extra Precision (XP) docking methods, followed by pose processing with Molecular Mechanics Generalised Born Surface Area (MM/GBSA) calculations. This led to the identification of five potential inhibitors: L-histidinol phosphate (DB03997), L-gluconic acid (DB04304), 4-bromo-3-(carboxymethoxy)-5-(4-hydroxyphenyl)thiophene-2-carboxylic acid (DB07197), 3-O-methylfructose (DB02438), and glutamine hydroxamate (DB02446), with docking scores ranging from −7.96 to −5.58 kcal/mol and MM/GBSA scores between −26.23 and −1.00 kcal/mol. The study also included Density Functional Theory computations and pharmacokinetic profiling to assess these compounds’ suitability further, revealing promising results. Additionally, we conducted molecular interaction fingerprint analysis, revealing key residues involved in interactions, including 10LYS (Basic), 8LEU (non-polar), 7ASP (Acidic), and 7THR (Polar), indicating a mixed interaction profile. A 5 ns WaterMap analysis was used to identify optimal hydration sites and interaction patterns. Moreover, a 100 ns molecular dynamics (MD) simulation using the TIP3P water model in the NPT ensemble confirmed the stability of the protein-ligand complexes, with acceptable deviations, fluctuations, and intermolecular interactions. MM/GBSA calculations on the simulation trajectories supported these findings by providing binding free energy and complex energy estimations for all protein-ligand complexes. Although these findings provide compelling computational evidence for haptoglobin inhibition, experimental studies must confirm its effectiveness before human use. |
| format | Article |
| id | doaj-art-6934c9835f3d4c57bd3e5911a36f72b7 |
| institution | DOAJ |
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| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemistry |
| spelling | doaj-art-6934c9835f3d4c57bd3e5911a36f72b72025-08-20T03:09:25ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462025-06-011310.3389/fchem.2025.16119721611972Integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma-linked inflammatory and haematological malignanciesAbdulaziz H. Al Khzem0Shaban Ahmad1Department of Pharmaceutical Chemistry, College of Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi ArabiaDepartment of Computer Science, Jamia Millia Islamia, New Delhi, IndiaElevated levels of haptoglobin are commonly observed in conditions characterised by an increased erythrocyte sedimentation rate which are acute-phase reactants. These conditions include infection, trauma, inflammation, hepatitis, amyloidosis, collagen diseases, lymphoma, leukaemia, as well as obstructive and biliary diseases. However, no significant drugs are currently available to manage these conditions, making therapeutic intervention crucial effectively. In this study, we performed an extensive screening of the DrugBank database against the human haptoglobin protein (PDB ID: 4X0L) using High-Throughput Virtual Screening (HTVS), Standard Precision and Extra Precision (XP) docking methods, followed by pose processing with Molecular Mechanics Generalised Born Surface Area (MM/GBSA) calculations. This led to the identification of five potential inhibitors: L-histidinol phosphate (DB03997), L-gluconic acid (DB04304), 4-bromo-3-(carboxymethoxy)-5-(4-hydroxyphenyl)thiophene-2-carboxylic acid (DB07197), 3-O-methylfructose (DB02438), and glutamine hydroxamate (DB02446), with docking scores ranging from −7.96 to −5.58 kcal/mol and MM/GBSA scores between −26.23 and −1.00 kcal/mol. The study also included Density Functional Theory computations and pharmacokinetic profiling to assess these compounds’ suitability further, revealing promising results. Additionally, we conducted molecular interaction fingerprint analysis, revealing key residues involved in interactions, including 10LYS (Basic), 8LEU (non-polar), 7ASP (Acidic), and 7THR (Polar), indicating a mixed interaction profile. A 5 ns WaterMap analysis was used to identify optimal hydration sites and interaction patterns. Moreover, a 100 ns molecular dynamics (MD) simulation using the TIP3P water model in the NPT ensemble confirmed the stability of the protein-ligand complexes, with acceptable deviations, fluctuations, and intermolecular interactions. MM/GBSA calculations on the simulation trajectories supported these findings by providing binding free energy and complex energy estimations for all protein-ligand complexes. Although these findings provide compelling computational evidence for haptoglobin inhibition, experimental studies must confirm its effectiveness before human use.https://www.frontiersin.org/articles/10.3389/fchem.2025.1611972/fullhaptoglobindrug design and discoverycomputational medicinal chemistrymolecular dockingbinding free energy |
| spellingShingle | Abdulaziz H. Al Khzem Shaban Ahmad Integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma-linked inflammatory and haematological malignancies Frontiers in Chemistry haptoglobin drug design and discovery computational medicinal chemistry molecular docking binding free energy |
| title | Integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma-linked inflammatory and haematological malignancies |
| title_full | Integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma-linked inflammatory and haematological malignancies |
| title_fullStr | Integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma-linked inflammatory and haematological malignancies |
| title_full_unstemmed | Integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma-linked inflammatory and haematological malignancies |
| title_short | Integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma-linked inflammatory and haematological malignancies |
| title_sort | integrative computational approaches identify haptoglobin inhibitors to modulate erythrocyte sedimentation rate in trauma linked inflammatory and haematological malignancies |
| topic | haptoglobin drug design and discovery computational medicinal chemistry molecular docking binding free energy |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2025.1611972/full |
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