A unique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies

Mayer, Dorica; Naylor, Christopher; Mot̨oc, Ioan; Marshall, Garland R.

doi:10.1007/bf01680553

Cited by 163 publications

(116 citation statements)

References 32 publications

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“…Hence the question of the most likely pharmacophore for ACE inhibition remains open and of interest to researchers. The present work provides further confirmation for an earlier proposal by Mayer et al (Mayer et al, 1987), using energy-minimized conformations (according to Tripos' Sybyl and Advanced Computation packages) and using ideal binding geometries for zinc. But the present work also proposes an alternative.…”

Section: Lessons Regarding Ace Inhibitionsupporting

confidence: 88%

“…The set of 28 pharmacophores can be condensed into a pair of distinct proposed pharmacophores for ACE inhibition. One of these pharmacophores is the same (modulo a small geometric perturbation) as the pharmacophore found in the first experiment, thus confirming the proposal of Mayer et al (Mayer et al, 1987). The second is an interesting alternative that deserves further attention.…”

Section: Overview Of the Experimentssupporting

confidence: 87%

“…Hypothesis 1: Given the conformations and zinc binding sites proposed by Mayer and colleagues (Mayer et al, 1987), as well as definitions of hydrogen acceptors, hydrogen donors, and hydrophobic groups, progol will re-discover the pharmacophore proposed by Mayer et al…”

Section: Experiments 1: a Blindfold Testmentioning

confidence: 99%

“…Many methods of pharmacophore identification have been described in the literature. In the active analogue approach (Mayer et al, 1987), it is necessary to identify the equivalent pharmacophore groups in each molecule in advance. Conformations of each of a series of active molecules are then sought which place these groups in a common spatial arrangement.…”

Section: Pharmacophoresmentioning

confidence: 99%

“…A pharmacophore was proposed for ACE inhibition eleven years ago by Mayer and colleagues (Mayer et al, 1987). Earlier modeling studies had investigated the ACE pharmacophore, but based on a small number of compounds (Hassell et al, 1982, Andrews et al, 1985.…”

Section: Overview Of the Experimentsmentioning

confidence: 99%

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et al. 1998

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Abstract. This paper presents a case study of a machine-aided knowledge discovery process within the general area of drug design. Within drug design, the particular problem of pharmacophore discovery is isolated, and the Inductive Logic Programming (ILP) system progol is applied to the problem of identifying potential pharmacophores for ACE inhibition. The case study reported in this paper supports four general lessons for machine learning and knowledge discovery, as well as more specific lessons for pharmacophore discovery, for Inductive Logic Programming, and for ACE inhibition. The general lessons for machine learning and knowledge discovery are as follows.1. An initial rediscovery step is a useful tool when approaching a new application domain.2. General machine learning heuristics may fail to match the details of an application domain, but it may be possible to successfully apply a heuristic-based algorithm in spite of the mismatch.3. A complete search for all plausible hypotheses can provide useful information to a user, although experimentation may be required to choose between competing hypotheses. 4. A declarative knowledge representation facilitates the development and debugging of background knowledge in collaboration with a domain expert, as well as the communication of final results.

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Section: Lessons Regarding Ace Inhibitionsupporting

confidence: 88%

Section: Overview Of the Experimentssupporting

confidence: 87%

Section: Experiments 1: a Blindfold Testmentioning

confidence: 99%

Section: Pharmacophoresmentioning

confidence: 99%

Section: Overview Of the Experimentsmentioning

confidence: 99%

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et al. 1998

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A comparative molecular field analysis study of obtusifoliol 14α-methyl demethylase inhibitors

Bargar¹,

Secor²,

Markley³

et al. 1999

Pestic. Sci.

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This report describes the development of a Comparative Molecular Field Analysis (CoMFA) model from a set of obtusifoliol 14a-methyl demethylase (DM) inhibitors to aid in the design of herbicides targeting sterol biosynthesis. CoMFA is a three-dimensional (3-D) quantitative structure± activity relationship (QSAR) method that is useful in the probing of receptor binding sites when experimental structure data are unavailable. Conformational analysis and SAR of some rigid and active analogs were used to build the initial model using the active analog hypothesis. The model was subsequently used to design compounds that retain the active site shape requirements, but incorporate physical properties that favor soil-applied herbicidal action. In addition, a second-generation CoMFA model incorporating the newly designed inhibitors was developed and represents the current understanding of the DM binding site. This model was derived from a pharmacophore developed from two methods, the active analog approach as well as from the Catalyst program. The fact that two independent methods produced a similar pharmacophore strengthens the validity of the model.

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