The Good, the Bad, and the Twisted Revisited: An Analysis of Ligand Geometry in Highly Resolved Protein–Ligand X‑ray Structures

An analysis of the rotatable bond geometry of drug-like ligand models is reported for high-resolution (–1 by calculation. An unusual torsional geometry is more prevalent where the fit to electron density is not perfect. Multiple low-strain conformer bindings were observed in 21% of the set and, it is suggested, may also lie behind many of the 35% of single-occupancy cases, where a poor fit to the e-density was found. It is concluded that multiple conformer ligand binding is an under-recognized phenomenon in structure-based drug design and that there is a need for more robust crystallographic refinement methods to better handle such cases.