7bgc
From Proteopedia
human butyrylcholinesterase in complex with a tacrine-methylanacardate hybrid inhibitor
Structural highlights
Disease[CHLE_HUMAN] Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:177400]. BChE deficiency is a metabolic disorder characterized by prolonged apnoea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency. BChE deficiency is a multifactorial disorder. The hereditary condition is transmitted as an autosomal recessive trait. Function[CHLE_HUMAN] Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.[1] [2] Publication Abstract from PubMedThe multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 muM), confirming the design rationale. Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease.,Rossi M, Freschi M, de Camargo Nascente L, Salerno A, de Melo Viana Teixeira S, Nachon F, Chantegreil F, Soukup O, Prchal L, Malaguti M, Bergamini C, Bartolini M, Angeloni C, Hrelia S, Soares Romeiro LA, Bolognesi ML J Med Chem. 2021 Apr 22;64(8):4972-4990. doi: 10.1021/acs.jmedchem.1c00048. Epub , 2021 Apr 8. PMID:33829779[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||||||
