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Pushing the limits of detection of weak binding using fragment based drug discovery: identification of new cyclophilin binders

DOI: 10.1016/j.jmb.2017.06.016 DOI Help

Authors: Charis Georgiou (University of Edinburgh) , Iain Mcnae (University of Edinburgh) , Martin Wear (University of Edinburgh) , Harris Ioannidis (University of Edinburgh) , Julien Michel (University of Edinburgh) , Malcolm Walkinshaw (University of Edinburgh)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: June 2017
Diamond Proposal Number(s): 7613 , 9487

Abstract: Fragment Based Drug Discovery (FBDD) is an increasingly popular method to identify novel small-molecule drug candidates. One of the limitations of the approach is the difficulty of accurately characterizing weak binding events. This work reports a combination of X-ray diffraction, surface plasmon resonance (SPR) experiments and molecular dynamics (MD) simulations, for the characterisation of binders to different isoforms of the cyclophilin (Cyp) protein family. Although several Cyp inhibitors have been reported in the literature, it has proven challenging to achieve high binding selectivity for different isoforms of this protein family. The present studies have led to the identification of several structurally novel fragments that bind to diverse Cyp isoforms in distinct pockets with low millimolar dissociation constants. A detailed comparison of the merits and drawbacks of the experimental and computational techniques is presented, and emerging strategies for designing ligands with enhanced isoform specificity are described.

Journal Keywords: PPIases; cyclophilin inhibitors; fragment based drug discovery; free energy calculations; protein – ligand X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine, Technique Development

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)