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Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space

Rudling, Axel; Gustafsson, Robert; Almlöf, Ingrid; Homan, Evert; Scobie, Martin; Warpman Berglund, Ulrika; Helleday, Thomas; Stenmark, Pål LU and Carlsson, Jens (2017) In Journal of Medicinal Chemistry 60(19). p.8160-8169
Abstract

Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 μM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar... (More)

Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 μM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Computer Simulation, Crystallography, X-Ray, DNA Repair Enzymes/chemistry, Drug Discovery/methods, Enzyme Inhibitors/chemistry, Humans, Ligands, Models, Molecular, Molecular Docking Simulation, Phosphoric Monoester Hydrolases/chemistry, Protein Binding, Small Molecule Libraries, Structure-Activity Relationship
in
Journal of Medicinal Chemistry
volume
60
issue
19
pages
8160 - 8169
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85031290078
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.7b01006
language
English
LU publication?
no
id
db2bd9a8-f911-4763-8e01-668a3b338561
date added to LUP
2019-04-30 07:53:42
date last changed
2019-10-15 07:02:27
@article{db2bd9a8-f911-4763-8e01-668a3b338561,
  abstract     = {<p>Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 μM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.</p>},
  author       = {Rudling, Axel and Gustafsson, Robert and Almlöf, Ingrid and Homan, Evert and Scobie, Martin and Warpman Berglund, Ulrika and Helleday, Thomas and Stenmark, Pål and Carlsson, Jens},
  issn         = {1520-4804},
  keyword      = {Computer Simulation,Crystallography, X-Ray,DNA Repair Enzymes/chemistry,Drug Discovery/methods,Enzyme Inhibitors/chemistry,Humans,Ligands,Models, Molecular,Molecular Docking Simulation,Phosphoric Monoester Hydrolases/chemistry,Protein Binding,Small Molecule Libraries,Structure-Activity Relationship},
  language     = {eng},
  month        = {10},
  number       = {19},
  pages        = {8160--8169},
  publisher    = {The American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.7b01006},
  volume       = {60},
  year         = {2017},
}