A simple procedure for the derivation of electron density based surfaces of drug-receptor complexes from a combination of X-ray data and theoretical calculations.

Bioorganic & Medicinal Chemistry
Stefan MebsPeter Luger

Abstract

To contribute to an understanding of biological recognition and interaction, an easy-to-use procedure was developed to generate and display molecular surfaces and selected electron density based surface properties. To overcome the present limitations to derive electron densities of macromolecules, the considered systems were reduced to appropriate substructures around the active centers. The combination of experimental X-ray structural information and aspherical atomic electron density data from theoretical calculations resulted in properties like the electrostatic potential and the Hirshfeld surface which allowed a study of electronic complementarity and the identification of sites and strengths of drug-receptor interactions. Applications were examined for three examples. The anilinoquinazoline gefitinib (Iressa(R)) belongs to a new class of anticancer drugs that inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). In the second example, the interaction of epoxide inhibitors with the main protease of the SARS coronavirus was investigated. Furthermore, the progesterone receptor complex was examined. The quantitative analysis of hydrogen bonding in the chosen substructure systems follows a progres...Continue Reading

References

Feb 10, 2000·Acta Crystallographica. Section D, Biological Crystallography·D HoussetC Lecomte
Aug 6, 2000·Acta Crystallographica. Section B, Structural Science·E EspinosaC Lecomte
Nov 1, 2000·Cell·J Schlessinger
Aug 28, 2002·The Journal of Biological Chemistry·Jennifer StamosCharles Eigenbrot
Aug 24, 2006·Acta Crystallographica. Section A, Foundations of Crystallography·Anatoliy VolkovLouis J Farrugia
Dec 14, 2006·Acta Crystallographica. Section D, Biological Crystallography·Jan GruberMartin E M Noble
Jan 24, 2007·Acta Crystallographica. Section D, Biological Crystallography·Anatoliy VolkovPhilip Coppens
Feb 16, 2007·Acta Crystallographica. Section A, Foundations of Crystallography·Bartosz ZarychtaChristian Jelsch
May 21, 2008·Acta Crystallographica. Section B, Structural Science·Christian B HübschlePeter Luger
Apr 1, 2009·Cellular and Molecular Life Sciences : CMLS·Stephan EllmannPamela L Strissel

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Citations

May 13, 2014·Acta Crystallographica. Section D, Biological Crystallography·Maura MalińskaPaulina M Dominiak
Oct 5, 2016·Acta Crystallographica Section B, Structural Science, Crystal Engineering and Materials·Chinnasamy KalaiarasiPoomani Kumaradhas
Feb 23, 2013·Organic & Biomolecular Chemistry·Peter LugerReinhold Tacke

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Methods Mentioned

BETA
X-ray

Software Mentioned

XD
tonto
XDPROP
GaussView
invariom
Moliso

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