Structures of Human Acetylcholinesterase in Complex with Pharmacologically Important Ligands

Cheung, Jonah; Rudolph, M.; Burshteyn, F.; Cassidy, M.; Gary, E.; Love, J.; Franklin, Matthew C.; Height, J.J.

doi:10.1021/jm300871x

Cited by 999 publications

(858 citation statements)

References 23 publications

Supporting

Mentioning

771

Contrasting

Unclassified

Order By: Relevance

“…4, 21.5, 22.5, 22.9, 23.1, 24.2, 24.6, 26.8, 28.5, 28.7, 29.0, 29.6, 30.4, 30.8, 31.6, 33.5, 41.8, 49.3, 114.8, 115.4, 119.7, 122.8, 122.9, 123.7, 124.2, 128.0, 128.6, 129.3, 146.7, 146.8, 151.0, 151.1, 157.6, 157.8; (R) 6,7,6,7,6,7,6,7, The heterodimers (R)-and (S)-3d were obtained according to general procedure to give a yellow solid 01-3.17 (m, 3H), 3.37-3.57 (m, 4H), 3.81-4.07 (sl, 2H), 7.18-7.38 (m, 2H), 7.43-7.58 (m, 1H), 7.78-8.01 (m, 4H); 13 C NMR (75 MHz, CDCl 3 ) d 21. 6, 22.9, 23.2, 24.3, 24.9, 26.9, 28.9, 29.2, 31.0, 34.1, 42.6, 49.5, 49.6, 115.2, 116.0, 118.5, 120.3, 122.9, 123.7, 124.2, 124.7, 127.8, 128.4, 128.8, 134.0, 147.5, 148.5, 150.7, 150.8, 158.5, 159.5; (R) 58 The inhibitors from the representative conformations of AChE (i) interact with the CAS, (ii) interact with the PAS, and (iii) are similar to the tacrine inhibitor. The exception is the 1J07, which is complexed with an inhibitor that interacts exclusively with PAS.…”

Section: Methodsmentioning

confidence: 99%

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Lopes¹,

Costa²,

Ceschi³

et al. 2017

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

Cholinesterase enzymes are important targets for the therapy of Alzheimer's disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo-and heterodimers of bis (7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedländer cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl 3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo-and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds. Keywords: bistacrine, chiral, cholinesterases, synthesis, molecular docking IntroductionAlzheimer's disease (AD) is one of the leading causes of death among elderly people in the World, and its treatment remains a challenge for the pharmaceutical community. Nearly a million new cases per year it is expected to emerge by 2050.1,2 The proposed cholinergic hypothesis of cognitive impairment has been accepted for decades to explain AD and is characterized by the loss of cholinergic basal forebrain, and their projections to the cerebral cortices. 2,3 According to this hypothesis, the memory and cognitive decline well-marked in AD result from a deficit of the important neurotransmitter acetylcholine (ACh). In this context, the inhibition of cholinesterase enzymes (ChEs) that are responsible for the hydrolyses of ACh emerge as a symptomatic treatment to relieve these symptoms. [4][5][6] The current therapeutic options for AD are limited to three inhibitors of acetylcholinesterase (AChEI):4-8 donepezil (Aricept ® ), rivastigmine (Exelon ® ) and galantamine (Razadyne ® , Reminyl ® ). In addition, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda ® ) is also used. [9][10][11] However, none of these therapeutic options represent a real cure.The cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes which are found in the central nervous system (CNS) and catalyze the hydrolysis of ACh efficiently but at different rates. [9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity. 13,14 The acetylcholine binding site of AChE is located at the base of a deep hydrophobic channel measuring Lopes et al. 2219 Vol. 28, No. 11, 2017 approximately 20 Å in length. It is formed by a catalytic anionic site (CAS) composed by the catalytic triad Ser200, His440 and Gl...

show abstract

Section: Methodsmentioning

confidence: 99%

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Lopes¹,

Costa²,

Ceschi³

et al. 2017

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…The 3D-QSAR model and molecular docking were carried out with the software package SYBYL-X2.0 [18]. The crystal structures of human AChE complexed with donepezil (E20) and human BACE-1 complexed with AZD3835 (32D) were retrieved from PDB with corresponding entry code 4EY7 [19] and 4B05 [20], respectively (http://www.pdb.org/). In order to compare the results from docking protocols and obtain good docking score, the donepezil and AZD3835 ligands were removed from donepezil-AChE complex and AZD3835-BACE-1 complex, respectively, and then the hydrogen atoms were added on the AChE and BACE-1 enzymes, respectively.…”

Section: Methodsmentioning

confidence: 99%

MTDLs Design on AChE (Acetylcholinesterase) and β-Secretase (BACE-1): 3D-QSAR and Molecular Docking Studies

Shi¹,

Tu²,

Sheng³

et al. 2015

JPP

View full text Add to dashboard Cite

To find promising new multitargeted AD (Alzheimer's disease) inhibitors, the 3D-QSAR (three-dimensional quantitative structure-activity relationship) model for 32 AD inhibitors was established by using the CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity index analysis) methods. Results showed that the CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient (q 2 ) and a non-cross-validated coefficient (R 2 ), and the binding modes obtained by molecular docking were in agreement with the 3D-QSAR results, which suggests that the present 3D-QSAR model has good predictive capability to guide the design and structural modification of novel multitargeted AD inhibitors. Meanwhile, we found that one side of inhibitory molecule should be small group so that it would be conductive to enter the gorge to interact with the catalytic active sites of AChE (acetylcholinesterase), and the other side of inhibitory molecule should be large group so that it would be favorable for interaction with the peripheral anionic site of AChE. Furthermore, based on the 3D-QSAR model and the binding modes of AChE and β-secretase (BACE-1), the designed molecules could both act on dual binding sites of AChE (catalytic and peripheral sites) and dual targets (AChE and BACE-1). We hope that our results could provide hints for the design of new multitargeted AD derivatives with more potency and selective activity.

show abstract

“…Compared with the various Fas2-AChE complexes, which show tightly bound Fas2 at the PAS with a fully occluded gorge entrance and no back door channel in the crystal state (14,23,(71)(72)(73)(74) and display residual activities not exceeding a few percent in solution (15,(75)(76)(77), the semi-occluding Fab410 position at the BfAChE PAS and presumed higher opening frequency of the back door channel in the complex are likely to account for the greater residual activity of the Fab410-BfAChE complex (Table 1). However, the presence of bound Fab410 at the BfAChE PAS raises a question as to whether both conformations of Tyr 442 preexist in unliganded BfAChE or whether one of them is correlated with (i.e.…”

Section: Evidence For Coexisting Open and Closed States Of A Back Doomentioning

confidence: 99%

“…An average surface area of ϳ900 Å 2 is buried on each partner of the complex with the Fab410 H and L chains contributing ϳ500 and ϳ400 Å 2 , respectively, and the binding interface is 73 and Pro 76 all in the long ⍀ loop. For its part, the Fab410 L chain is positioned near the tip of the long ⍀ loop in BfAChE, away from the gorge entrance, with CDR L3 contributing most of the binding interface (Fig.…”

Section: Evidence For Coexisting Open and Closed States Of A Back Doomentioning

confidence: 99%

Crystal Structure of Snake Venom Acetylcholinesterase in Complex with Inhibitory Antibody Fragment Fab410 Bound at the Peripheral Site

Bourne

Renault

Marchot

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: mAb Elec410 inhibits acetylcholinesterase by binding at the active site gorge entrance. Results: Biochemical and structural characterization of Fab410-bound acetylcholinesterase reveals residual catalytic activity, coexisting open/closed states of a back door channel, and a semi-occluded gorge entrance. Conclusion: Bound antibody restricts substrate access through the gorge and may modulate back door opening. Significance: This unique molecular template with high frequency back door opening refines our understanding of acetylcholinesterase catalysis.

show abstract

Structures of Human Acetylcholinesterase in Complex with Pharmacologically Important Ligands

Cited by 999 publications

References 23 publications

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

MTDLs Design on AChE (Acetylcholinesterase) and β-Secretase (BACE-1): 3D-QSAR and Molecular Docking Studies

Crystal Structure of Snake Venom Acetylcholinesterase in Complex with Inhibitory Antibody Fragment Fab410 Bound at the Peripheral Site

Contact Info

Product

Resources

About