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Fragment Based Drug Discovery(FBDD) isan 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 draw backs of the experimental and computational techniques is presented, and emerging strategies for designing ligands with enhanced isoform specificity are described.