Ligand promiscuity in drug design is generally associated with either a desired polypharmacology or unwanted non-selective binding and side-effects. In fragment-based drug design (FBDD), however, promiscuity is considered with interest as fragments with low specificity can be advantageous for finding many screening hits. To extend our understanding of how fragments bind to diverse protein targets and whether conserved-mode binders can be recognized based on their intrinsic properties, we analyzed the interactions of crystallographic protein-fragment complexes in the Protein Data Bank (PDB).<br/>Whereas fragments and their druglike superstructures binding to the same target show a high degree of binding mode conservation, we find that the majority of multi-target fragments shows non-conserved binding modes, even if they bind in a similar conformation or similar protein targets. Surprisingly, fragment properties alone are not able to predict whether a fragment will exhibit a versatile or conserved binding mode, emphasizing the interplay between protein and fragment features during a binding event and the importance of structure-based modelling.

Fragment promiscuity and binding mode variability

254th National Meeting (2017)

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