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

Gao, Lin; Liao, Wen Bo; Chan, Chung-Hwey; Wu, Yi-Hian; Tsai, Hou-Jen; Hsieh, Chi-Wei

doi:10.1002/jbt.20045

Cited by 15 publications

(17 citation statements)

References 33 publications

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“…The fractions of unionised species calculated from pK a data are important descriptors used in the TPAM model when describing partial transcelluar and paracelluar permeability models. In addition, it has been used for estimating the acidity or basicity of a compound's functional groups that might affect active binding sites [3,30]. McFarland et al used pK a and logP to generate QSAR mode to predict potencies of 15 known macrolides of diverse structures and found that these physicochemical properties are major determinants of macrolide antibacterial in vitro and in vivo potencies [31].…”

Section: A Relevant Descriptor In Qsar Modelsmentioning

confidence: 99%

High-throughput pK_ascreening and prediction amenable for ADME profiling

Wan

Ulander

2006

Expert Opinion on Drug Metabolism & Toxicology

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Recent technological advances have made it possible for several new pK(a) assays to be used in drug screening. In this review, a critical overview is provided of current new methodologies for high-throughput screening and prediction of pK(a). Typical applications of using pK(a )constants and charge state for absorption, distribution, metabolism and excretion (ADME) profiling and quantitative structure-activity relationship modelling complements the methodological comparisons and discussions. The experimental methods discussed include high-throughput screening of pK(a) by multiplexed capillary with ultraviolet absorbance detection on a 96-capillary format instrument, capillary electrophoresis and mass spectrometry (CEMS) based on sample pooling, determination of pK(a) by pH gradient high-performance liquid chromatography, and measurement of pK(a) by a mixed-buffer liner pH gradient system. Comparisons of the different experimental assays are made with emphasis on the newly developed CEMS method. The current status and recent progress in computational approaches to pK(a) prediction are also discussed. In particular, the accuracy limits of simple fragment-based approaches as well as quantum mechanical methods are addressed. Examples of pK(a) prediction from in-house drug candidates as well as commercially available drug molecules are shown and an outline is provided for how drug discovery companies can integrate experiments with computational approaches for increased applications for ADME profiling.

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Section: A Relevant Descriptor In Qsar Modelsmentioning

confidence: 99%

High-throughput pK_ascreening and prediction amenable for ADME profiling

Wan

Ulander

2006

Expert Opinion on Drug Metabolism & Toxicology

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“…Among such inhibitors are various alkyl-and aryl-carbamates and ureas responsible for the mechanism-based inhibition of enzymes by formation of carbamyl enzymes. Among these enzymes are fatty acid amide hydrolase (34,42), monoacylglycerol lipase (25), acetyl cholinesterase (21), and Pseudomonas species lipase (22). In all of these cases the enzyme forms a covalent carbamyl enzyme via the active-site serine, including in some cases via a substituted piperidine carbamyl link (25) as is the case with NXL104.…”

Section: Vol 54 2010 Inactivation Of ␤-Lactamases By Nxl104 5135mentioning

confidence: 99%

Mechanistic Studies of the Inactivation of TEM-1 and P99 by NXL104, a Novel Non-β-Lactam β-Lactamase Inhibitor

Stachyra¹,

Péchereau²,

Bruneau³

et al. 2010

Antimicrob Agents Chemother

134

125

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NXL104 is a potent inhibitor of class A and C serine ␤-lactamases, including KPC carbapenemases. Native and NXL104-inhibited TEM-1 and P99 ␤-lactamases analyzed by liquid chromatography-electrospray ionization-time of flight mass spectrometry revealed that the inactivated enzymes formed a covalent adduct with NXL104. The principal inhibitory characteristics of NXL104 against TEM-1 and P99 ␤-lactamases were determined, including partition ratios, dissociation constants (K), rate constants for deactivation (k 2 ), and reactivation rates. NXL104 is a potent inhibitor of TEM-1 and P99, characterized by high carbamylation efficiencies (k 2 /K of 3.7 ؋ 10 5 M ؊1 s ؊1 for TEM-1 and 1 ؋ 10 4 M ؊1 s ؊1 for P99) and slow decarbamylation. Complete loss of ␤-lactamase activity was obtained at a 1/1 enzyme/NXL104 ratio, with a k 3 value (rate constant for formation of product and free enzyme) close to zero for TEM-1 and P99. Fifty percent inhibitory concentrations (IC 50 s) were evaluated on selected ␤-lactamases, and NXL104 was shown to be a very potent inhibitor of class A and C ␤-lactamases. IC 50 s obtained with NXL104 (from 3 nM to 170 nM) were globally comparable on the ␤-lactamases CTX-M-15 and SHV-4 with those obtained with the comparators (clavulanate, tazobactam, and sulbactam) but were far lower on TEM-1, KPC-2, P99, and AmpC than those of the comparators. In-depth studies on TEM-1 and P99 demonstrated that NXL104 had a comparable or better affinity and inactivation rate than clavulanate and tazobactam and in all cases an improved stability of the covalent enzyme/inhibitor complex.

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“…(7) ( Figure 6 and Table 2). The δ value of 0.08 for pK i -E s -π correlation indicates that the inhibitors 1-8 with less bulky ester moieties are easier to pass by the trumpet mouth of the enzyme (Figure 7) [7,37,[40][41][42][43].…”

Section: Discussionmentioning

confidence: 98%

“…The first step is protonation of inhibitor due to the basicity for the inhibitors [19,21,40]. The second step (K i ) is the formation of the enzyme-inhibitor tetrahedral intermediate.…”

Section: Discussionmentioning

confidence: 99%

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

Cited by 15 publications

References 33 publications

High-throughput pK_ascreening and prediction amenable for ADME profiling

High-throughput pK_ascreening and prediction amenable for ADME profiling

Mechanistic Studies of the Inactivation of TEM-1 and P99 by NXL104, a Novel Non-β-Lactam β-Lactamase Inhibitor

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

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

Cited by 15 publications

References 33 publications

High-throughput pKascreening and prediction amenable for ADME profiling

High-throughput pKascreening and prediction amenable for ADME profiling

Mechanistic Studies of the Inactivation of TEM-1 and P99 by NXL104, a Novel Non-β-Lactam β-Lactamase Inhibitor

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

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Product

Resources

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High-throughput pK_ascreening and prediction amenable for ADME profiling

High-throughput pK_ascreening and prediction amenable for ADME profiling