PMID- 30989572
OWN - NLM
STAT- MEDLINE
DCOM- 20200616
LR  - 20210109
IS  - 1573-4951 (Electronic)
IS  - 0920-654X (Linking)
VI  - 33
IP  - 5
DP  - 2019 May
TI  - Visualizing protein-ligand binding with chemical energy-wise decomposition 
      (CHEWD): application to ligand binding in the kallikrein-8 S1 Site.
PG  - 461-475
LID - 10.1007/s10822-019-00200-4 [doi]
AB  - 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.
FAU - Raza, Saad
AU  - Raza S
AD  - Computational Biology Lab, National Center for Bioinformatics, Quaid-i-Azam 
      University Islamabad, Islamabad, 45320, Pakistan.
AD  - Centre for Computational Chemistry, School of Chemistry, University of Bristol, 
      Bristol, UK.
FAU - Ranaghan, Kara E
AU  - Ranaghan KE
AD  - Centre for Computational Chemistry, School of Chemistry, University of Bristol, 
      Bristol, UK.
FAU - van der Kamp, Marc W
AU  - van der Kamp MW
AD  - Centre for Computational Chemistry, School of Chemistry, University of Bristol, 
      Bristol, UK.
AD  - School of Biochemistry, Biomedical Sciences Building, University of Bristol, 
      University Walk, Bristol, BS8 1TD, UK.
AD  - BrisSynBio Synthetic Biology Research Centre, Life Sciences Building, University 
      of Bristol, Tyndall Avenue, Bristol, BS8 1TQ, UK.
FAU - Woods, Christopher J
AU  - Woods CJ
AD  - Centre for Computational Chemistry, School of Chemistry, University of Bristol, 
      Bristol, UK.
AD  - BrisSynBio Synthetic Biology Research Centre, Life Sciences Building, University 
      of Bristol, Tyndall Avenue, Bristol, BS8 1TQ, UK.
FAU - Mulholland, Adrian J
AU  - Mulholland AJ
AD  - Centre for Computational Chemistry, School of Chemistry, University of Bristol, 
      Bristol, UK. adrian.mulholland@bristol.ac.uk.
AD  - BrisSynBio Synthetic Biology Research Centre, Life Sciences Building, University 
      of Bristol, Tyndall Avenue, Bristol, BS8 1TQ, UK. 
      adrian.mulholland@bristol.ac.uk.
FAU - Azam, Syed Sikander
AU  - Azam SS
AD  - Computational Biology Lab, National Center for Bioinformatics, Quaid-i-Azam 
      University Islamabad, Islamabad, 45320, Pakistan. syedazam2008@gmail.com.
LA  - eng
GR  - BB/L01386X/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - BB/M026280/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - BB/ M000354/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190415
PL  - Netherlands
TA  - J Comput Aided Mol Des
JT  - Journal of computer-aided molecular design
JID - 8710425
RN  - 0 (Ligands)
RN  - EC 3.4.21.- (KLK8 protein, human)
RN  - EC 3.4.21.- (Kallikreins)
SB  - IM
MH  - Binding Sites
MH  - Drug Design
MH  - Drug Discovery
MH  - Humans
MH  - Kallikreins/*antagonists & inhibitors/chemistry/metabolism
MH  - Ligands
MH  - Molecular Docking Simulation
MH  - Molecular Dynamics Simulation
MH  - Protein Binding
MH  - Software
MH  - Thermodynamics
OTO - NOTNLM
OT  - Binding energy
OT  - Chemical energy-wise decomposition
OT  - Kallikrein 8
OT  - Molecular dynamics simulation
OT  - WaterSwap
EDAT- 2019/04/17 06:00
MHDA- 2020/06/17 06:00
CRDT- 2019/04/17 06:00
PHST- 2018/10/23 00:00 [received]
PHST- 2019/04/05 00:00 [accepted]
PHST- 2019/04/17 06:00 [pubmed]
PHST- 2020/06/17 06:00 [medline]
PHST- 2019/04/17 06:00 [entrez]
AID - 10.1007/s10822-019-00200-4 [pii]
AID - 10.1007/s10822-019-00200-4 [doi]
PST - ppublish
SO  - J Comput Aided Mol Des. 2019 May;33(5):461-475. doi: 10.1007/s10822-019-00200-4. 
      Epub 2019 Apr 15.