butyrylcholinesterase
butyrylcholinesterase
Overview
Butyrylcholinesterase (BChE; also known as pseudocholinesterase, plasma cholinesterase, or non-specific cholinesterase) is a serine hydrolase enzyme encoded by the BCHE gene in humans. It belongs to the cholinesterase family and preferentially hydrolyzes butyrylcholine, though it can also act on acetylcholine and a broad range of choline esters. Unlike its close paralog acetylcholinesterase (AChE), which is concentrated at neuromuscular junctions and synapses, BChE is expressed widely across tissues including the liver, plasma, intestine, and brain. Structurally, BChE possesses a catalytic triad (Ser-His-Glu) within a deep, gorge-shaped active site, flanked by a peripheral anionic site and a choline-binding pocket—features that are exploited extensively in drug design efforts.
BChE plays a complex and context-dependent role in cholinergic neurotransmission. Under normal physiological conditions, it contributes modestly to the hydrolysis of acetylcholine; however, in advanced Alzheimer's disease (AD), AChE activity declines markedly while BChE activity progressively compensates, making BChE an increasingly important therapeutic target as neurodegeneration advances. Beyond neurological disease, BChE is implicated in lipid metabolism, glucose homeostasis linked to insulin resistance, and detoxification of xenobiotics. Its expression has also been identified in certain tumor microenvironments, extending its relevance beyond neuropharmacology into oncology. These diverse roles have made BChE the subject of intense multidisciplinary research, spanning synthetic medicinal chemistry, natural product pharmacology, parasitology, and cancer biology.
Focus of Latest Publications
Recent publications have continued to position butyrylcholinesterase as an important target in Alzheimer’s disease research, particularly in studies seeking dual cholinesterase inhibition alongside acetylcholinesterase. Several synthetic series were designed and evaluated specifically for BChE activity, including flavonoid-fused aminoquinolines, chiral anthranilic diamide derivatives, thieno[3,2-d]pyrimidine hybrids, benzothiazole-linked oxadiazoles, coumarin-based derivatives, and benzimidazole analogs. Across these reports, BChE inhibition was commonly assessed in vitro and supported by molecular docking, with some studies also incorporating molecular dynamics, MM-GBSA calculations, and ADMET or ADME profiling to prioritize lead compounds.
Among the most potent BChE-directed findings, the chromeno[4,3-b]quinoline derivative (±)-7-amino-6-phenyl-6H-chromeno[4,3-b]quinoline showed strong human BChE inhibition with an IC50 of 0.096 μM, outperforming its AChE activity. Chiral anthranilic diamide derivatives also showed significant BChE inhibition, with compounds 7a and 7b displaying nanomolar potency and enzyme-specific stereoselectivity; docking and simulation studies supported 7a as the stronger BChE binder. Thieno[3,2-d]pyrimidine-phenolic Mannich base hybrids were reported as dual cholinesterase inhibitors with low-nanomolar Ki values, and compounds 5 and 9 were highlighted for strong BChE inhibition. In the benzothiazole-oxadiazole series, K11 and K7 showed notable BChE inhibitory activity comparable to the reference drug, while coumarin derivative 10f demonstrated significant BuChE inhibition at 303 nM.
Other studies extended BChE-focused work into broader multifunctional anti-Alzheimer strategies. The benzimidazole analog IMS48 inhibited BChE with an IC50 of 1.85 μM and, in an in vivo rat model, improved behavioral outcomes while reducing markers associated with neurodegeneration and inflammation. Hydrazide-hydrazone indole congeners were also screened against BChE as part of a multi-target program that included AChE, BACE-1, MAO-A, MAO-B, and COX-2; compounds 3c, 3f, and 3k were advanced based on their overall biological profiles. In parallel, plant-derived extracts from fruit tree leaves and Epimedium pubigerum were reported to inhibit BChE alongside other enzymes, with molecular docking suggesting that identified phytochemicals may contribute to cholinergic system modulation.
Beyond Alzheimer’s disease, butyrylcholinesterase appeared in a bioinformatics study of cervical cancer, where BCHE was among the genes proposed as potential therapeutic targets linked to calcium signaling, cAMP, and inflammation-related pathways. Although this work did not test BChE enzymatic inhibition directly, it reinforced the enzyme’s broader relevance in disease-associated target discovery. Overall, the recent literature emphasizes BChE as a recurring target in dual cholinesterase inhibitor design, with several new scaffolds showing promising potency, selectivity, and computational support for further development.