The Effect of Halogen-to-Hydrogen Bond Substitution on Human Aldose Reductase Inhibition.
The effect of halogen-to-hydrogen bond substitution on the binding energetics and biological activity of a human aldose reductase inhibitor has been studied using X-ray crystallography, IC50 measurements, advanced binding free energy calculations, and simulations. The replacement of Br or I atoms by an amine (NH2) group has not induced changes in the original geometry of the complex, which made it possible to study the isolated features of selected noncovalent interactions in a biomolecular complex.
†Institute of Organic Chemistry and Biochemistry (IOCB) and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Jindřich
J
Fanfrlík
‡Department of Integrative Biology, IGBMC, CNRS, INSERM, UdS, 1 rue Laurent Fries 67404, Illkirch CEDEX, France.
Francesc X
FX
Ruiz
†Institute of Organic Chemistry and Biochemistry (IOCB) and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Aneta
A
Kadlčíková
†Institute of Organic Chemistry and Biochemistry (IOCB) and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Jan
J
Řezáč
‡Department of Integrative Biology, IGBMC, CNRS, INSERM, UdS, 1 rue Laurent Fries 67404, Illkirch CEDEX, France.
Alexandra
A
Cousido-Siah
‡Department of Integrative Biology, IGBMC, CNRS, INSERM, UdS, 1 rue Laurent Fries 67404, Illkirch CEDEX, France.
André
A
Mitschler
†Institute of Organic Chemistry and Biochemistry (IOCB) and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Susanta
S
Haldar
†Institute of Organic Chemistry and Biochemistry (IOCB) and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Martin
M
Lepšík
†Institute of Organic Chemistry and Biochemistry (IOCB) and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.|§Institute of Neuroscience and Medicine (INM-9) and Institute for Advanced Simulations (IAS-5), Forschungszentrum Jülich GmbH, 52428 Jülich, Germany.
Michal H
MH
Kolář
†Institute of Organic Chemistry and Biochemistry (IOCB) and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Pavel
P
Majer
‡Department of Integrative Biology, IGBMC, CNRS, INSERM, UdS, 1 rue Laurent Fries 67404, Illkirch CEDEX, France.
Alberto D
AD
Podjarny
†Institute of Organic Chemistry and Biochemistry (IOCB) and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.|∥Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Palacký University, Olomouc, 771 46 Olomouc, Czech Republic.
Pavel
P
Hobza
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular
D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase