Visualizing protein–ligand binding with chemical energy-wise decomposition (CHEWD): application to ligand binding in the kallikrein-8 S1 Site
| Autor: | Christopher J. Woods, Saad Raza, Adrian J. Mulholland, Syed Sikander Azam, Marc W. van der Kamp, Kara E. Ranaghan |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Binding energy BrisSynBio Molecular Dynamics Simulation Ligands 01 natural sciences Chemical energy-wise decomposition Molecular dynamics Molecular dynamics simulation 0103 physical sciences Drug Discovery Humans Physical and Theoretical Chemistry Binding site WaterSwap Serine protease Binding Sites 010304 chemical physics biology urogenital system Chemistry Bristol BioDesign Institute Kallikrein Ligand (biochemistry) Kallikrein 8 0104 chemical sciences Computer Science Applications Molecular Docking Simulation SYNTHETIC BIOLOGY 010404 medicinal & biomolecular chemistry Drug Design biology.protein Thermodynamics Kallikreins KALLIKREIN 8 Software Protein Binding circulatory and respiratory physiology Protein ligand |
| Zdroj: | Raza, S, Ranaghan, K, Van der Kamp, M, Woods, C, Mulholland, A & Azam, S S 2019, ' Visualizing protein–ligand binding with chemical energy-wise decomposition (CHEWD) : application to ligand binding in the kallikrein-8 S1 Site ', Journal of Computer-Aided Molecular Design, vol. 33, no. 5, pp. 461-475 . https://doi.org/10.1007/s10822-019-00200-4 |
| ISSN: | 1573-4951 0920-654X |
| DOI: | 10.1007/s10822-019-00200-4 |
| Popis: | Kallikrein-8, a serine protease, is a target for structure-based drug design due to its therapeutic potential in treating Alzheimer’s disease and is also useful as a biomarker in ovarian cancer. We present a binding assessment of ligands to kallikrein-8 using a residue-wise decomposition of the binding energy. Binding of four putative inhibitors of kallikrein-8 is investigated through molecular dynamics simulation and ligand binding energy evaluation with two methods (MM/PBSA and WaterSwap). For visualization of the residue-wise decomposition of binding energies, chemical energy-wise decomposition or CHEWD is introduced as a plugin to UCSF Chimera and Pymol. CHEWD allows easy comparison between ligands using individual residue contributions to the binding energy. Molecular dynamics simulations indicate one ligand binds stably to the kallikrein-8 S1 binding site. Comparison with other members of the kallikrein family shows that residues responsible for binding are specific to kallikrein-8. Thus, ZINC02927490 is a promising lead for development of novel kallikrein-8 inhibitors. |
| Databáze: | OpenAIRE |
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