Acetylcholinesterase inhibition by the ketone transition state analogs phenoxyacetone and 1-halo-3-phenoxy-2-propanones

Dafforn, Alan; Neenan, John P.; Ash, Charles E.; Betts, Laurie; Finke, Julie M.; Garman, Jeffrey A.; Rao, M. Prasad; Walsh, Kenneth A.; Williams, Robert R.

doi:10.1016/0006-291x(82)90679-9

Cited by 7 publications

(4 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These compounds have dissociation constants, or K\' values, in the micromolar range, which on adjustment for ketone hydration give K\ values in the nanomolar range. This observation is consistent with previous reports of AChE inhibition by ketones (Allen & Abeles, 1989;Brodbeck et al, 1979;Dafforn et al, 1976Dafforn et al, ,1982Gelb et al, 1985;Linderman et al, 1988). As the size and polarizability of the meta substituent are increased, time-dependent inhibition is observed.…”

Section: Resultssupporting

confidence: 93%

Molecular Recognition in Acetylcholinesterase Catalysis: Free-Energy Correlations for Substrate Turnover and Inhibition by Trifluoro Ketone Transition-State Analogs

et al. 1994

View full text Add to dashboard Cite

Ten meta-substituted aryl trifluoromethyl ketones (m-XC6H4COCF3; X = H, CH3, CF3, C2H5, isopropyl, t-butyl, NH2, NMe2, N+Me3, NO2) have been evaluated as inhibitors of acetylcholinesterases from Electrophorus electricus and Torpedo californica. Trifluoro ketones that have small meta substituents (X = H, CH3, CF3, C2H5, NH2, NO2) are rapid reversible inhibitors, whereas the remaining compounds in this study show time-dependent inhibition. Dissociation constants (Ki values) for these compounds span a range of approximately 10(7)-fold, with trifluoroacetophenone (X = H) being the least potent and m-(N,N,N-trimethylammonio)trifluoroacetophenone (X = Me3N+) being the most potent inhibitor. For the latter compound Ki values are 1.5 and 15 fM for inhibitions of the respective acetylcholinesterases (Nair, H. K., Lee, K., & Quinn, D. M. (1993) J. Am. Chem. Soc. 115, 9939-9941). Linear correlations of log(kcat/Km) for substrate turnover versus pKi of inhibitors have slopes of approximately 0.6, which suggest that aryl trifluoro ketones bind to AChE in a manner that structurally resembles transition states in the acylation stage of catalysis. Substituent variation in the inhibitors allows one to gauge the importance for AChE function of molecular recognition in the quaternary ammonium binding locus of the active site. This locus is frequently termed the "anionic site" and consists of E199, W84, and perhaps Y130 and F330. Correlations of pKi versus hydrophobicity constant are linear for alkyl and trifluoromethyl substituents but fail for nitrogen-containing substituents. However, three-dimensional correlations of pKi versus sigma m and molar refractivity of substituents indicate that dispersion interactions in the anionic locus contribute approximately 10(5)-fold (delta delta G = 7 kcal mol-1) to the above-mentioned 10(7)-fold range of inhibitor potencies. The remaining approximately 100-fold arises from the inductive electronic effects of substituents on the stability of the tetrahedral adduct that forms between the ketone carbonyl of inhibitors and S200 in the esteratic locus of the active site. Values of k(on), the second-order rate constant for binding of time-dependent inhibitors, monitor a diffusion-controlled process. Moreover, k(on) for the quaternary ammonio inhibitor is 20-70-fold higher than for inhibitors that have uncharged meta substituents, which likely reflects the effect of the electrical field of AChE on ligand and substrate binding.

show abstract

Section: Resultssupporting

confidence: 93%

Molecular Recognition in Acetylcholinesterase Catalysis: Free-Energy Correlations for Substrate Turnover and Inhibition by Trifluoro Ketone Transition-State Analogs

et al. 1994

View full text Add to dashboard Cite

show abstract

“…The set of vapors contains three vapors selected as simulants of these materials. Methanesulfonyl fluoride is an irreversible enzyme inhibitor and, as such, exhibits biological activity similar to the organophosphorus insecticides (21). Dimethylacetamide has solubility properties that are similar to these materials, as indicated by the solubility pa- rameter values in Table I.…”

Section: Resultsmentioning

confidence: 98%

Correlation of surface acoustic wave device coating responses with solubility properties and chemical structure using pattern recognition

Ballantine¹,

Rose²,

Grate³

et al. 1986

Anal. Chem.

211

140

View full text Add to dashboard Cite

“…Though one cannot produce a crystal structure of an enzyme complexed with its substrate in the transition state, due to the short lifetime of the transition state versus the time required for X-ray data collection, one can exploit the high affinity of transition state analogs. ,, A number of reports have described transition state analog inhibitors of AChE. − One such analog, m -( N , N , N -trimethylammonio)-2,2,2-trifluoroacetophenone (TMTFA), first reported by Brodbeck et al ., has recently been studied in depth. , The K i for inhibition of TcAChE by TMTFA is 15 fM, which is lower by only 3 orders of magnitude than the estimated affinity for the transition state, and is about 10 orders of magnitude higher than the affinity of the substrate in the ES complex, as estimated from the K m . It seemed, therefore, that TMTFA could serve as a ligand of choice for visualizing the important interactions within the active site which are responsible for the remarkable catalytic activity of AChE.…”

Section: Introductionmentioning

confidence: 99%

“…32,35,36 A number of reports have described transition state analog inhibitors of AChE. [37][38][39][40][41] One such analog, m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone (TMTFA), first reported by Brodbeck et al, 38 has recently been studied in depth. 42,43 The K i for inhibition of TcAChE by TMTFA is 15 fM, which is lower by only 3 orders of magnitude than the estimated affinity for the transition state, and is about 10 orders of magnitude higher than the affinity of the substrate in the ES complex, as estimated from the K m .…”

Section: Introductionmentioning

confidence: 99%

The X-ray Structure of a Transition State Analog Complex Reveals the Molecular Origins of the Catalytic Power and Substrate Specificity of Acetylcholinesterase

et al. 1996

View full text Add to dashboard Cite

The structure of a complex of Torpedo californica acetylcholinesterase with the transition state analog inhibitor m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone has been solved by X-ray crystallographic methods to 2.8 Å resolution. Since the inhibitor binds to the enzyme about 1010-fold more tightly than the substrate acetylcholine, this complex provides a visual accounting of the enzyme−ligand interactions that provide the molecular basis for the catalytic power of acetylcholinesterase. The enzyme owes about 8 kcal mol-1 of the 18 kcal mol-1 of free energy of stabilization of the acylation transition state to interactions of the quaternary ammonium moiety with three water molecules, with the carboxylate side chain of E199, and with the aromatic side chains of W84 and F330. The carbonyl carbon of the trifluoroketone function interacts covalently with S200 of the S200−H440−E327 catalytic triad. The operation of this triad as a general acid−base catalytic network probably provides 3−5 kcal mol-1 of the free energy of stabilization of the transition state. The remaining 5−7 kcal mol-1 of transition state stabilization probably arises from tripartite hydrogen bonding between the incipient oxyanion and the NH functions of G118, G119, and A201. The acetyl ester hydrolytic specificity of the enzyme is revealed by the interaction of the CF3 function of the transition state analog with a concave binding site comprised of the residues G119, W233, F288, F290, and F331. The highly geometrically convergent array of enzyme−ligand interactions visualized in the complex described herein envelopes the acylation transition state and sequesters it from solvent, this being consistent with the location of the active site at the bottom of a deep and narrow gorge.

show abstract

Acetylcholinesterase inhibition by the ketone transition state analogs phenoxyacetone and 1-halo-3-phenoxy-2-propanones

Cited by 7 publications

References 9 publications

Molecular Recognition in Acetylcholinesterase Catalysis: Free-Energy Correlations for Substrate Turnover and Inhibition by Trifluoro Ketone Transition-State Analogs

Molecular Recognition in Acetylcholinesterase Catalysis: Free-Energy Correlations for Substrate Turnover and Inhibition by Trifluoro Ketone Transition-State Analogs

Correlation of surface acoustic wave device coating responses with solubility properties and chemical structure using pattern recognition

The X-ray Structure of a Transition State Analog Complex Reveals the Molecular Origins of the Catalytic Power and Substrate Specificity of Acetylcholinesterase

Contact Info

Product

Resources

About