Design, synthesis, biological evaluation, and modeling of a non-carbohydrate antagonist of the myelin-associated glycoprotein.
Broad modifications of various positions of the minimal natural epitope recognized by the myelin-associated glycoprotein (MAG), a blocker of regeneration of neurite injuries, produced sialosides with nanomolar affinities. However, important pharmacokinetic issues, for example, the metabolic stability of these sialosides, remain to be addressed. For this reason, the novel non-carbohydrate mimic 3 was designed and synthesized from (-)-quinic acid. For the design of 3, previously identified beneficial modifications of side chains of Neu5Ac were combined with the replacement of the ring oxygen by a methylene group and the substitution of the C(4)-OH by an acetamide. Although docking experiments to a homology model of MAG revealed that mimic 3 forms all but one of the essential hydrogen bonds identified for the earlier reported lead 2, its affinity was substantially reduced. Extensive molecular-dynamics simulation disclosed that the missing hydrogen bond of the former C(8)-OH leads to a change of the orientation of the side chain. As a consequence, an important hydrophobic contact is compromised leading to a loss of affinity.
Schwardt
Oliver
O
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
Koliwer-Brandl
Hendrik
H
Zimmerli
Raphael
R
Mesch
Stefanie
S
Rossato
Gianluca
G
Spreafico
Morena
M
Vedani
Angelo
A
Kelm
Sørge
S
Ernst
Beat
B
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002241:Carbohydrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D012794:Sialic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001549:Benzamides; D002241:Carbohydrates; D003509:Cyclohexanecarboxylic Acids; D018992:Myelin-Associated Glycoprotein; D012794:Sialic Acids; D019158:N-Acetylneuraminic Acid