title: In situ selection of lead compounds by click chemistry: target-guided optimization of acetylcholinesterase inhibitors.
abstract: The target-guided, in situ click chemistry approach to lead discovery has been successfully employed for discovering acetylcholinesterase (AChE) inhibitors by incubating a selected enzyme/tacrine azide combination with a variety of acetylene reagents that were not previously known to interact with the enzyme's peripheral binding site. The triazole products, formed by the enzyme, were identified by HPLC-mass spectrometry analysis of the crude reaction mixtures. The target-guided lead discovery search was also successful when performed with reagent mixtures containing up to 10 components. From 23 acetylene reagents, the enzyme selected two phenyltetrahydroisoquinoline (PIQ) building blocks that combined with the tacrine azide within the active center gorge to form multivalent inhibitors that simultaneously associate with the active and peripheral binding sites. These new inhibitors are up to 3 times as potent as our previous phenylphenanthridinium-derived compounds, and with dissociation constants as low as 33 femtomolar, they are the most potent noncovalent AChE inhibitors known. In addition, the new compounds lack a permanent positive charge and aniline groups and possess fewer fused aromatic rings. Remarkably, despite the high binding affinity, the enzyme displayed a surprisingly low preference for one PIQ enantiomer over the other.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Krasiński
authors.forename: Zoran
authors.initials: Z
authors.lastname: Radić
authors.forename: Roman
authors.initials: R
authors.lastname: Manetsch
authors.forename: Jessica
authors.initials: J
authors.lastname: Raushel
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
authors.forename: K Barry
authors.initials: KB
authors.lastname: Sharpless
authors.forename: Hartmuth C
authors.initials: HC
authors.lastname: Kolb
mesh_terms: D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D051379:Mice; D010617:Phenanthridines / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D010617:Phenanthridines; D014230:Triazoles; D013619:Tacrine