Multi‐target Fragments Display Versatile Binding Modes

Promiscuity is an interesting concept in fragment‐based drug design as fragments with low specificity can be advantageous for finding many screening hits. We present a PDB‐wide analysis of multi‐target fragments and their binding mode conservation. Focussing on multi‐target fragments, we found that the majority 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.