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Visualizing protein–ligand binding with chemical energy-wise decomposition (CHEWD): application to ligand binding in the kallikrein-8 S1 Site

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)461-475
Number of pages15
JournalJournal of Computer-Aided Molecular Design
Volume33
Issue number5
Early online date15 Apr 2019
DOIs
DateAccepted/In press - 5 Apr 2019
DateE-pub ahead of print - 15 Apr 2019
DatePublished (current) - 15 May 2019

Abstract

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.

    Research areas

  • Kallikrein 8, Molecular dynamics simulation, Binding energy, WaterSwap, Chemical energy-wise decomposition

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer at https://link.springer.com/article/10.1007%2Fs10822-019-00200-4 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 1 MB, PDF-document

    Embargo ends: 15/04/20

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