Structure Report for: 4A16

Carletti, E., Colletier, J.P., Nachon, F., Weik, M., Ronco, C., Jean, L., Renard, P.Y.

Title: Huprine derivatives as sub-nanomolar human acetylcholinesterase inhibitors: from rational design to validation by X-ray crystallography
Ronco C, Carletti E, Colletier JP, Weik M, Nachon F, Jean L, Renard PY
Ref: ChemMedChem, 7:400, 2012 : PubMed
Abstract


ESTHER: Ronco_2012_ChemMedChem_7_400
PubMedSearch: Ronco 2012 ChemMedChem 7 400
PubMedID: 22052791
Gene_locus related to this paper: mouse-ACHE
Inhibitor(s) related to this paper: H34

Abstract

This complete study - from rational design to validation by X-ray crystallography allowed us to discover two sub-nanomolar hAChE inhibitors (430 and 530 pM) grafted with an easily derivatized linker directed toward the AChE peripheral site. The crystal structure of mouse AChE in complex with compound 4 was solved and confirms the favorable position of the triazole in the active site gorge, paving the way for a new class of bifunctional ligands. ***LongTextEnd*** Paper "Ronsted_2012_BMC.Evol.Biol_12_182" Author "Ronsted N" Author "Symonds MR" Author "Birkholm T" Author "Christensen SB" Author "Meerow AW" Author "Molander M" Author "Molgaard P" Author "Petersen G" Author "Rasmussen N" Author "van Staden J" Author "Stafford GI" Author "Jager AK" Year "2012" Title "Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of Amaryllidaceae" Journal "BMC Evol Biol" Volume "12" Page "182" "" Medline "22978363" Abstract "Ronsted_2012_BMC.Evol.Biol_12_182" LongText "Ronsted_2012_BMC.Evol.Biol_12_182" BACKGROUND: During evolution, plants and other organisms have developed a diversity of chemical defences, leading to the evolution of various groups of specialized metabolites selected for their endogenous biological function. A correlation between phylogeny and biosynthetic pathways could offer a predictive approach enabling more efficient selection of plants for the development of traditional medicine and lead discovery. However, this relationship has rarely been rigorously tested and the potential predictive power is consequently unknown. RESULTS: We produced a phylogenetic hypothesis for the medicinally important plant subfamily Amaryllidoideae (Amaryllidaceae) based on parsimony and Bayesian analysis of nuclear, plastid, and mitochondrial DNA sequences of over 100 species. We tested if alkaloid diversity and activity in bioassays related to the central nervous system are significantly correlated with phylogeny and found evidence for a significant phylogenetic signal in these traits, although the effect is not strong. CONCLUSIONS: Several genera are non-monophyletic emphasizing the importance of using phylogeny for interpretation of character distribution. Alkaloid diversity and in vitro inhibition of acetylcholinesterase (AChE) and binding to the serotonin reuptake transporter (SERT) are significantly correlated with phylogeny. This has implications for the use of phylogenies to interpret chemical evolution and biosynthetic pathways, to select candidate taxa for lead discovery, and to make recommendations for policies regarding traditional use and conservation priorities.