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

J Comput Aided Mol Des. 2019 May;33(5):461-475. doi: 10.1007/s10822-019-00200-4. Epub 2019 Apr 15.

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.

Keywords: Binding energy; Chemical energy-wise decomposition; Kallikrein 8; Molecular dynamics simulation; WaterSwap.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Design
  • Drug Discovery
  • Humans
  • Kallikreins / antagonists & inhibitors*
  • Kallikreins / chemistry
  • Kallikreins / metabolism
  • Ligands
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Software
  • Thermodynamics

Substances

  • Ligands
  • KLK8 protein, human
  • Kallikreins