title: The design, synthesis, and biological evaluation of analogues of the serine-threonine protein phosphatase 1 and 2A selective inhibitor microcystin LA: rational modifications imparting PP1 selectivity.
abstract: Based on the results from previously reported molecular modeling analyses of the interactions between the inhibitor microcystin and the serine-threonine protein phosphatases 1 and 2A, we have designed analogues of microcystin LA with structural modifications intended to impart PP1 selectivity. The synthesis of several first generation analogues followed by inhibition assays revealed that all three are PP1-selective, as predicted. Although the observed selectivities are modest, one of the designed analogues is more selective for PP1 than any known small molecule inhibitor.
authors.affiliation: Department of Chemistry, University of California at Irvine, 92697, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Aggen
authors.forename: J M
authors.initials: JM
authors.lastname: Humphrey
authors.forename: C M
authors.initials: CM
authors.lastname: Gauss
authors.forename: H B
authors.initials: HB
authors.lastname: Huang
authors.forename: A C
authors.initials: AC
authors.lastname: Nairn
authors.forename: A R
authors.initials: AR
authors.lastname: Chamberlin
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D052998:Microcystins; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054645:Protein Phosphatase 1; D013055:Spectrophotometry, Infrared; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D052998:Microcystins; D010456:Peptides, Cyclic; C049865:cyanoginosin-LA; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1