Similarities and differences between crystal and enzyme environmental effects on the electron density of drug molecules

Kleemiss, Florian; Wieduwilt, Erna K.; Hupf, Emanuel; Shi, Ming W.; Stewart, Scott G.; Jayatilaka, Dylan; Turner, Michael J.; Sugimoto, Kunihisa; Nishibori, Eiji; Schirmeister, Tanja; Schmidt, Thomas C.; Engels, Bernd; Grabowsky, Simon (2021). Similarities and differences between crystal and enzyme environmental effects on the electron density of drug molecules. Chemistry - a European journal, 27(10), pp. 3407-3419. Wiley-VCH 10.1002/chem.202003978

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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 0.1e are shifted between these two environments in total. However, this has non‐negligible consequences for derived properties.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Kleemiss, Florian and Grabowsky, Simon

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0947-6539

Publisher:

Wiley-VCH

Language:

English

Submitter:

Simon Grabowsky

Date Deposited:

02 Feb 2021 14:09

Last Modified:

17 Feb 2021 01:34

Publisher DOI:

10.1002/chem.202003978

PubMed ID:

33090581

BORIS DOI:

10.48350/150766

URI:

https://boris.unibe.ch/id/eprint/150766

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