Similarities and Differences between Crystal and Enzyme Environmental Effects on the Electron Density of Drug Molecules

Florian Kleemiss, Erna K. Wieduwilt, Emanuel Hupf, Ming W. Shi, Scott G. Stewart, Dylan Jayatilaka, Michael J. Turner, Kunihisa Sugimoto, Eiji Nishibori, Tanja Schirmeister, Thomas C. Schmidt, Bernd Engels, Simon Grabowsky

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3407-3419
Number of pages13
JournalChemistry - A European Journal
Volume27
Issue number10
DOIs
Publication statusPublished - 15 Feb 2021

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