Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain

Gavuzzo, Enrico; Pomponi, Massimiliano

doi:10.1002/jbt.10026

Cited by 4 publications

(1 citation statement)

References 17 publications

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“…Since the binding of cage amines on PAS only depends on the bulkiness of the inhibitors [37], the δ value of 0.44 strongly suggests that the binding between PAS and protonated carbamates 1 occurs in the K S1 step (Figure 4). In other words, bulkily substituted inhibitors [7,40,41] are difficult to bind onto the narrow entrance (PAS) of the enzyme active site gorge [8][9][10] for the K S1 step. For K S2 step, the ρ * value of −0.4 implies that the binding of the carbamate carbonyl oxygen to OAH generates a partial positive charge on the carbamate carbonyl carbon (Figure 4), and the ψ value of 0.27 implies that hydrophobic inhibitors are easier to pass through the hydrophobic loop [31] of the enzyme active site gorge than hydrophilic inhibitors (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Quantitative structure-activity relationships for the pre-steady state acetylcholinesterase inhibition by carbamates

Gao

Liao

Chan

et al. 2005

J. Biochem. Mol. Toxicol.

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4-Nitrophenyl-N-substituted carbamates (1) are characterized as pseudosubstrate inhibitors of acetylcholinesterase. The first step is formation of the enzyme-inhibitor tetrahedral intermediate with the inhibition constant (Ki), the second step is formation of the carbamyl enzyme with the carbamylation constant (kc), and the third step is hydrolysis of the carbamyl enzyme with decarbamylation constant (kd). According to pre-steady state kinetics the Ki step is divided further into two steps: (1) formation of the enzyme-inhibitor complex with the dissociation constant (KS) and (2) formation of the enzyme-inhibitor tetrahedral intermediate from the complex with the equilibrium constant (k2/k-2). Since the inhibitors are protonated in pH 7.0 buffer solution, the virtual dissociation constant (KS') of the enzyme-protonated inhibitor complex can be calculated from the equation, -log KS'=-log KS-pKa + 14. The -logKS, -log KS', log k2, and log k-2 values are multiply linearly correlated with the Jave equation (log(k/k0)=rho*sigma* + deltaEs + psi pi). For -log KS'-sigma*-Es)pi-correlation, the rho* value of -0.4 indicates that the enzyme-protonated inhibitor complexes have more positive charges than the protonated inhibitors, the delta value of 0.44 suggests that the bulkily substituted inhibitors lessen the reaction due to the difficulty of the inhibitors to enter the narrow enzyme active site gorge, and the psi value of 0.27 implies that the inhibitors with hydrophobic substituents accelerate the inhibitors entering the active site gorge of the enzyme. For log k2/k-2,-sigma*-Es-pi-correlation, the rho* value of 1.1 indicates that the enzyme-protonated inhibitor tetrahedral intermediates have more negative charges than the enzyme-protonated inhibitor complexes, the delta value of 0.15 suggests that the bulkily substituted inhibitors are difficult to bind into a small acyl binding site of the enzyme, and the psi value of -0.3 implies that the inhibitors with hydrophobic substituents resist binding to the hydrophilic acyl binding site of the enzyme.

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Section: Resultsmentioning

confidence: 99%

Quantitative structure-activity relationships for the pre-steady state acetylcholinesterase inhibition by carbamates

Gao

Liao

Chan

et al. 2005

J. Biochem. Mol. Toxicol.

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Probing the peripheral anionic site of acetylcholinesterase with quantitative structure activity relationships for inhibition by biphenyl‐4‐acyoxylate‐4′‐N‐Butylcarbamates

Gao

Chen

Yeh

et al. 2005

J Biochem & Molecular Tox

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Biphenyl-4-acyoxylate-4'-N-butylcarbamates 1-8 are synthesized from 4,4'-biphenol and are characterized as the pseudosubstrate inhibitors of acetylcholinesterase. In other words, the inhibitors bind to the enzyme and react with the enzyme to form the tetrahedral intermediates for the K(i) steps, and then the tetrahedral intermediates exclude the leaving groups to form a common N-butycarbamyl enzyme intermediate for the k(c) steps. Due to a linear character of the 4,4'-biphenyl moiety, the 4'-N-butylcarbamate moieties of the inhibitors react with the Ser200 residue of the enzyme while the 4-acyoxylate moieties of the inhibitors, on the other hand, should fit in the peripheral anionic site of the enzyme, which is located at the mouth of the deep active site gorge. Thus, carbamates with varied acyl substituents at the 4-position of the biphenyl ring are good candidates for probing the quantitative structure activity relationships for the peripheral anionic site of the enzyme. The fact that the pK(i), log k(c), and log K(i) values are correlated with neither the Taft substituent constant (sigma*) nor the Taft steric constant (E(s)) indicates that the 4-acyoxylate moieties of the inhibitors are too far away from the reaction center. However, the pK(i), log k(c), and log K(i) values are linearly correlated with the Hansch hydrophobicity constant, pi. The intensity constants (psi) for these correlations are 0.16, -0.035, and 0.13, respectively. These results indicate that interactions between the 4-acyoxylate groups of the inhibitors and the peripheral anionic site of the enzyme are mainly hydrophobic ones. The correlation results are slightly improved by using the two-parameter correlations with the Taft substituent steric constant, E(s), and pi. For pK(i), log k(c), and log K(i)-E(s)-pi correlations, the psi values are 0.21, -0.021, and 0.19, respectively; the intensity constants for steric effect (delta) are 0.08, 0.022, and 0.10, respectively. Besides hydrophobic interactions, the two-parameter correlations also suggest that little steric hindrance occurs for the bulkier inhibitors to pass by the peripheral anionic site of the enzyme.

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Construction of Chiral-Fused Tricyclic γ-Lactams via a trans-Perhydroindolic Acid-Catalyzed Asymmetric Domino Reaction

Shen

Liu

et al. 2017

Org. Lett.

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An asymmetric domino reaction was developed utilizing readily available cyclic α-dehydroamino ketones and aldehydes, which when subjected a 2-iodoxybenzoic acid (IBX)-mediated oxidation gives pyrrolidinone-containing tricyclic derivatives. trans-Perhydroindolic acid proved to be an efficient organocatalyst in this reaction (up to 94% yield, 99% ee, and >20:1 dr). The product could be conveniently converted to synthetically useful intermediates via simple transformations. A possible stereocontrolled process has been suggested according to X-ray crystallography studies.

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Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain

Cited by 4 publications

References 17 publications

Quantitative structure-activity relationships for the pre-steady state acetylcholinesterase inhibition by carbamates

Quantitative structure-activity relationships for the pre-steady state acetylcholinesterase inhibition by carbamates

Probing the peripheral anionic site of acetylcholinesterase with quantitative structure activity relationships for inhibition by biphenyl‐4‐acyoxylate‐4′‐N‐Butylcarbamates

Construction of Chiral-Fused Tricyclic γ-Lactams via a trans-Perhydroindolic Acid-Catalyzed Asymmetric Domino Reaction

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