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Fragment-based discovery and optimization of enzyme inhibitors by docking of commercial chemical space

DOI: 10.1021/acs.jmedchem.7b01006 DOI Help

Authors: Axel Rudling (Stockholm University) , Robert Gustafsson (Stockholm University) , Ingrid Almlöf (Karolinska institutet) , Evert J. Homan (Karolinska institutet) , Martin Scobie (Karolinska institutet) , Ulrika Warpman Berglund (Karolinska institutet) , Thomas Helleday (Karolinska institutet) , Pal Stenmark (Stockholm University) , Jens Carlsson (Uppsala University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 11265

Abstract: Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Despite that 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.

Journal Keywords: Fragment-based lead discovery; molecular docking; virtual screening; crystal structure; MTH1

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: BESSY; ESRF; Max-Lab; Swiss Light Source

Added On: 29/09/2017 15:47

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)