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The crystal interaction density is generally assumed to be a suitable measure of the polarization of a low‐molecular weight ligand inside an enzyme, but this approximation has seldomly been tested and has never been quantified before. In this study, we compare the crystal interaction density and the interaction electrostatic potential for a model compound of loxistatin acid (E64c) with those inside cathepsin B, in solution, and in vacuum. We apply QM/MM calculations and experimental quantum crystallography to show that the crystal interaction density is indeed very similar to the enzyme interaction density. Less than 0.1 e are shifted between these two environments in total. However, this difference has non‐negligible consequences for derived properties., The polarization of a drug molecule in an enzyme environment can be approximated by the polarization of the same molecule in its small‐molecule crystal structure. The degree of similarity is quantified in this study for a model compound of the protease inhibitor loxistatin acid in its interaction with cathepsin B by using interaction densities and interaction electrostatic potentials.

The synthesis of the new ligand bis(6-diphenylphosphinoacenaphth-5-yl)sulfoxide, [6-(Ph2P)-5-Ace-6](2)-SO (1), is presented along with six transition metal complexes thereof, namely,1 center dot MCl (M = Rh, Cu, Ag, Au) and1 center dot MCl2(M = Ni, Pd). Within these novel complexes, close metal-sulfur distances are observed and the nature of the M-S coordination, as well as the response of the(+)S-O(-)bond, are investigated in detail with a set of spectroscopic, crystallographic and real-space bonding indicators.