0000000000970337
AUTHOR
Thomas C. Schmidt
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.
Protocol for rational design of covalently interacting inhibitors.
The inhibition potencies of covalent inhibitors mainly result from the formation of a covalent bond to the enzyme during the inhibition mechanism. This class of inhibitors has essentially been ignored in previous target-directed drug discovery projects because of concerns about possible side effects. However, their advantages, such as higher binding energies and longer drug-target residence times moved them into the focus of recent investigations. While the rational design of non-covalent inhibitors became standard the corresponding design of covalent inhibitors is still in its early stages. Potent covalent inhibitors can be retrieved from large compound libraries by covalent docking approa…
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 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