Fragment-based drug discovery 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 alchemical free energy calculations, surface plasmon resonance experiments and X-ray crystallography diffraction, for the characterization of binders to different isoforms of the cyclophilin (Cyp) protein family.<br/><br/>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 joint experimental/computational studies have led to the identification of several structurally novel fragments that bind to diverse pockets in the isoform CypA with low millimolar dissociation constants. A detailed comparison of the merits and drawbacks of the various techniques used will be presented, as well as lessons learned from the discovered fragments for the design of next-generation Cyclophilin ligands.

Application of free energy calculation methods to fragment-based drug discovery: Identification of new cyclophilin binders

255th National Meeting (2018)

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