0000000001300600
AUTHOR
Ming W. Shi
Approaching an experimental electron density model of the biologically active trans ‐epoxysuccinyl amide group—Substituent effects vs. crystal packing
The trans-epoxysuccinyl amide group as a biologically active moiety in cysteine protease inhibitors such as loxistatin acid E64c has been used as a benchmark system for theoretical studies of environmental effects on the electron density of small active ingredients in relation to their biological activity. Here, the synthesis and the electronic properties of the smallest possible active site model compound are reported to close the gap between the unknown experimental electron density of trans-epoxysuccinyl amides and the well-known function of related drugs. Intramolecular substituent effects are separated from intermolecular crystal packing effects on the electron density, which allows us…
Electrostatic complementarity in pseudoreceptor modeling based on drug molecule crystal structures: the case of loxistatin acid (E64c)
After a long history of use as a prototype cysteine protease inhibitor, the crystal structure of loxistatin acid (E64c) is finally determined experimentally using intense synchrotron radiation, providing insight into how the inherent electronic nature of this protease inhibitor molecule determines its biochemical activity. Based on the striking similarity of its intermolecular interactions with those observed in a biological environment, the electrostatic potential of crystalline E64c is used to map the characteristics of a pseudo-enzyme pocket.
Similarities and differences between crystal and enzyme environmental effects on the electron density of drug molecules
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. Howeve…
CCDC 1498221: Experimental Crystal Structure Determination
Related Article: Ming W. Shi, Scott G. Stewart, Alexandre N. Sobolev, Birger Dittrich, Tanja Schirmeister, Peter Luger, Malte Hesse, Yu-Sheng Chen, Peter R. Spackman,Mark A. Spackman, Simon Grabowsky|2017|J.Phys.Org.Chem.|30|e3683|doi:10.1002/poc.3683
CCDC 977799: Experimental Crystal Structure Determination
Related Article: Ming W. Shi, Alexandre N. Sobolev, Tanja Schirmeister, Bernd Engels, Thomas C. Schmidt, Peter Luger, Stefan Mebs, Birger Dittrich, Yu-Sheng Chen, Joanna M. Bąk, Dylan Jayatilaka, Charles S. Bond, Michael J. Turner, Scott G. Stewart, Mark A. Spackman and Simon Grabowsky|2015|New J.Chem.|39|1628|doi:10.1039/C4NJ01503G
CCDC 2024395: Experimental Crystal Structure Determination
Related Article: 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|2021|Chem.-Eur.J.|27|3407|doi:10.1002/chem.202003978
CCDC 1498219: Experimental Crystal Structure Determination
Related Article: Ming W. Shi, Scott G. Stewart, Alexandre N. Sobolev, Birger Dittrich, Tanja Schirmeister, Peter Luger, Malte Hesse, Yu-Sheng Chen, Peter R. Spackman,Mark A. Spackman, Simon Grabowsky|2017|J.Phys.Org.Chem.|30|e3683|doi:10.1002/poc.3683
CCDC 1498220: Experimental Crystal Structure Determination
Related Article: Ming W. Shi, Scott G. Stewart, Alexandre N. Sobolev, Birger Dittrich, Tanja Schirmeister, Peter Luger, Malte Hesse, Yu-Sheng Chen, Peter R. Spackman,Mark A. Spackman, Simon Grabowsky|2017|J.Phys.Org.Chem.|30|e3683|doi:10.1002/poc.3683