title: Design, synthesis, biological evaluation, and modeling of a non-carbohydrate antagonist of the myelin-associated glycoprotein.
abstract: 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.
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwardt
authors.forename: Hendrik
authors.initials: H
authors.lastname: Koliwer-Brandl
authors.forename: Raphael
authors.initials: R
authors.lastname: Zimmerli
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mesch
authors.forename: Gianluca
authors.initials: G
authors.lastname: Rossato
authors.forename: Morena
authors.initials: M
authors.lastname: Spreafico
authors.forename: Angelo
authors.initials: A
authors.lastname: Vedani
authors.forename: Sørge
authors.initials: S
authors.lastname: Kelm
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: 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
chemical_list: D001549:Benzamides; D002241:Carbohydrates; D003509:Cyclohexanecarboxylic Acids; D018992:Myelin-Associated Glycoprotein; D012794:Sialic Acids; D019158:N-Acetylneuraminic Acid