5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: A Potent and Centrally-Selective Inhibitor of Acetylcholinesterase

Villalobos, Anabella; Tw, Butler; Ds, Chapin; Yl, Chen; Sb, DeMattos; Jl, Ives; Sb, Jones; Dr, Liston; Aa, Nagel; Dm, Nason

doi:10.1021/jm00015a002

Cited by 40 publications

(8 citation statements)

References 2 publications

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“…The recent E2020-AChE structure indicates that the indanone portion of E2020 is stacked against Trp 279 . A related inhibitor which replaces the indanone moiety of E2020 with a benzisoxazole may also enjoy a similar binding mode. Evidence for the affinity of uncharged hydrophobic residues for the AChE peripheral site was also provided by a study of toluene-tacrine heterodimers 3b − h (Scheme ) .…”

Section: Design and Synthesis Of Tacrine Heterodimersmentioning

confidence: 99%

Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand−Peripheral Site Interactions

et al. 1999

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Dimeric acetylcholinesterase (AChE) inhibitors containing a single 9-amino-1,2,3,4-tetrahydroacridine (tacrine) unit were constructed in an effort to further delineate structural requirements for optimal binding to the AChE peripheral site. Basic amines of differing hydrophobicity were selected as peripheral site ligands, and in each case, improvements in inhibitory potency and selectivity were seen relative to tacrine itself. AChE IC(50) values of the optimum dimers decrease significantly as the peripheral site ligand was permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-aminoquinoline > tacrine. Calculated desolvation free energies of the optimum dimers match the trend in IC(50) values, suggesting the importance of ligand hydrophobicity for effective cation-pi interaction with the peripheral site.

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Section: Design and Synthesis Of Tacrine Heterodimersmentioning

confidence: 99%

Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand−Peripheral Site Interactions

et al. 1999

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“…Its clinical efficacy, nevertheless, is limited owing to undesirable side effects, specially hepatotoxicity, and current research is focused on developing new inhibitors with improved activity and reduced adverse side effects as well as derivatives of physostigmine, N -benzylpiperidines, and xanthones . Attention has also been paid to huperzine A (HUP; see Figure ), an alkaloid found in Huperzia serrata traditionally utilized in Chinese folk medicine …”

Section: Introductionmentioning

confidence: 99%

Predicting Relative Binding Free Energies of Tacrine−Huperzine A Hybrids as Inhibitors of Acetylcholinesterase^§

1999

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The binding of the 9-methyl derivative of tacrine-huperzine A hybrid to Torpedo californica acetylcholinesterase (AChE) has been studied by computational methods. Molecular dynamics simulations have been performed for the AChE-drug complex considering two different ionization states of the protein and two different orientations of the drug in the binding pocket, which were chosen from a previous screening procedure. Analysis of structural fluctuations and of the pattern of interactions between drug and enzyme clearly favor one binding mode for the tacrine-huperzine A hydrid, which mixes effectively some of the binding features of tacrine and huperzine A. The differences in inhibitory activity for a series of related derivatives have been successfully predicted by free energy calculations, which reinforces the confidence in the binding mode and its usefulness for molecular modeling studies. The same techniques have been used to make de novo predictions for a new 3-fluoro-9-ethyl derivative, which can be used to verify a posteriori the goodness of the binding mode. Finally, we have also investigated the effect of replacing Phe300 in the Torpedo californica enzyme by Tyr, which is present in the human AChE. The results indicate that the Phe330-->Tyr mutation is expected to have little effect on the binding affinities. Overall, the whole of results supports the validity of the putative binding model to explain the binding of tacrine-huperzine A hybrids to AChE.

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“…ChEMBL-95020 presents a convincing superimposition of the isoxazole-containing tricycle [ 53 ] to the phthalimide of the training molecule. In a 2D sense, this prediction seems more surprising than the nominal 3D similarity value would suggest, but the actual disposition of chemical functionality and its mimicry of known ligands makes this not only an in-model prediction but a confident one that is also accurate.…”

Section: Resultsmentioning

confidence: 99%

Quantitative surface field analysis: learning causal models to predict ligand binding affinity and pose

Cleves

Jain

2018

J Comput Aided Mol Des

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We introduce the QuanSA method for inducing physically meaningful field-based models of ligand binding pockets based on structure-activity data alone. The method is closely related to the QMOD approach, substituting a learned scoring field for a pocket constructed of molecular fragments. The problem of mutual ligand alignment is addressed in a general way, and optimal model parameters and ligand poses are identified through multiple-instance machine learning. We provide algorithmic details along with performance results on sixteen structure-activity data sets covering many pharmaceutically relevant targets. In particular, we show how models initially induced from small data sets can extrapolatively identify potent new ligands with novel underlying scaffolds with very high specificity. Further, we show that combining predictions from QuanSA models with those from physics-based simulation approaches is synergistic. QuanSA predictions yield binding affinities, explicit estimates of ligand strain, associated ligand pose families, and estimates of structural novelty and confidence. The method is applicable for fine-grained lead optimization as well as potent new lead identification.

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5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: A Potent and Centrally-Selective Inhibitor of Acetylcholinesterase

Cited by 40 publications

References 2 publications

Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand−Peripheral Site Interactions

Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand−Peripheral Site Interactions

Predicting Relative Binding Free Energies of Tacrine−Huperzine A Hybrids as Inhibitors of Acetylcholinesterase^§

Quantitative surface field analysis: learning causal models to predict ligand binding affinity and pose

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5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: A Potent and Centrally-Selective Inhibitor of Acetylcholinesterase

Cited by 40 publications

References 2 publications

Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand−Peripheral Site Interactions

Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand−Peripheral Site Interactions

Predicting Relative Binding Free Energies of Tacrine−Huperzine A Hybrids as Inhibitors of Acetylcholinesterase§

Quantitative surface field analysis: learning causal models to predict ligand binding affinity and pose

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Predicting Relative Binding Free Energies of Tacrine−Huperzine A Hybrids as Inhibitors of Acetylcholinesterase^§