Molecular Pharmacology, a Basis for Drug Design

Ariëns, E. J.

doi:10.1007/978-3-0348-7059-7_8

Cited by 12 publications

(19 citation statements)

References 117 publications

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“…The following two steps involved in trimming are cycled through as many times as necessary to reduce the original HASL model to a subset of points, culminating in a HASLderived pharmacophore: (1) removal of those HASL points that currently represent the least significant partial pKx values (e.g., 10% of all HASL points in the current model that have partial p/Cj values nearest to zero) and (2) iterative distribution of the partial pK, values among the remaining lattice points to achieve the best correspondence between actual and predicted pKi. This approach is illustrated in Figure 4 wherein four HASL models (at resolutions of 2.0,2.5,3.0, and 3.5 A) were gradually reduced using a 10% trimming cycle as just described.…”

Section: Hasl Trimmingmentioning

confidence: 99%

“…Since the trimming cycle affects both properties in a similar manner, as evidenced by the relatively constant test set/learning set r2 ratio, the points The inhibitor/pharmacophore relationship can be further explored by examining which site points play the greatest role in determining inhibitor potency. This was done by superposing the strongest five inhibitors (1)(2)(3)(4)(5) and the weakest five inhibitors (80-84) on the 11-point pharmacophore and determining the minimum distance between a given site point and a corresponding atom type in the inhibitor molecule. Correspondence occurs when both the site point and the atom type share the same X-value.…”

Section: Predictivitymentioning

confidence: 99%

“…(Top) Inhibitor 1 superposed on the 11-point HASL-derived pharmacophore, illustrating site 6-hydroxyl and site 5-carbonyl correspondence. (Bottom) HIV-1 PR active site residues (magenta), inhibitor 1 (yellow), and site points(1)(2)(3)(4)(5)(6) superposed, illustrating site 5-water molecule and site 6-aspartyl carboxyl correspondence. Site points having //-values of 1,0, and -1 are colored red, white,…”

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confidence: 99%

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Pharmacophores from Binding Data

Doweyko¹

1994

J. Med. Chem.

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The application of HASL (hypothetical active site lattice) methodology has been successfully extended to generate putative pharmacophoric patterns in three dimensions capable of quantitatively predicting binding activity. The transformation of a HASL model to a pharmacophore is illustrated using pKi values published for 84 HIV-1 protease inhibitors. Starting with a HASL model generated at 2.00 A and containing 899 lattice points, a selective trimming process was used to identify significant lattice points. In this manner, a set of 11 points was found which represents a potential pharmacophoric pattern and predicts the pKi activity of the 84-inhibitor set with a correlation (r2) of 0.827. Furthermore, the locations of these points were found to coincide with a number of strategic binding areas within the known active site structure HIV-1 protease, thus providing a physical confirmation of their relevancy.

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Section: Hasl Trimmingmentioning

confidence: 99%

Section: Predictivitymentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacophores from Binding Data

Doweyko¹

1994

J. Med. Chem.

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“…First, since medicinal chemists are becoming more sensitive to the fact that optimal drug design must take into account Albert, 1973Ariens, 1966Ariens, 1971Palor, 1982Bundgaard, 1982Digenis and Swintosky, 1975Harper, 1959Harper, 1962Higuchi and Stella, 1975Roche, 1977Sinkula and Yalkowsky, 1975Sinkula, 1975Stella, 1973Stella, 1977Stella and Himmelstein, 1980Yalkowsky and Morozowich, 1980 the physical/chemical form of the drug as it pertains to stability, solubility, and other formulation factors, as well as pharmacokinetic factors, such as the transport properties of the drug, it is quite likely that the prodrug approach to optimizing those properties will become an integral part of basic drug design. As such, there is likely to be fewer examples where prodrugs will have to be used in a hindsighted manner to solve problems.…”

Section: Acknowledgementmentioning

confidence: 99%

Directed Drug Delivery

Borchardt¹,

Repta²,

Stella³

1985

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All rights reservedNo part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. PREFACEThis book is based on the proceedings of the symposium entitled "Directed Drug Delivery: A Multidisciplinary Problem," which was held in Lawrence, Kansas on October 17-19, 1984. The purpose of the symposium and this book is to focus on the multidisciplinary nature of drug delivery. Development of a successful drug delivery system requires contributions from various scientific disciplines, including pharmaceutical chemistry, analytical chemistry, medicinal chemistry, biochemistry, pharmacology, toxicology, and clinical medicine. The contents of this volume illustrate the importance of the various disciplines in identifying the problems and approaches for the development of a rational and effective drug delivery system. Thus the information provided herein will be of value not only to the pharmaceutical chemists who are responsible for dosage form design, but also to the pharmacokineticists, pharmacologists, and clinicians involved in biological evaluation of drug delivery systems. The volume should also be of interest to the analytical chemists who must provide technology to quantitcltively evaluate drug delivery. Additionally, this work will also interest the biochemists and medicinal chemists involved in drug discovery, since the drug delivery system often plays a major role in determining the success or failure of a new drug entity.Each speaker at the symposium was requested to contribute a chapter reviewing the contribution of their major discipline to the development of a successful drug delivery system. Topics covered in this volume include pharmacokinetics and pharmacodynamic factors (Section A) and physiological and biochemical factors (Section B) that influence directed drug delivery, various approaches to controlled and targeted drug delivery, including physical (SectionC) and biological (Section D) systems, as well as appropriate and important analytical chemistry topics (Section E).The individual chapters in this volume represent comprehensive, up-to-date reviews of the subject material. However, to gain maximum appreciation for the multidisciplinary nature of drug delivery, the editors suggest a thorough reading of the entire volume.

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“…For a very long time, the origin of the pharmacophore concept was attributed to Paul Ehrlich and specifically to his 1909 paper entitled “Über den jetzigen Stand der Chemoterapie” (Over the Current State of the Chemotherapy) . The primary source of linking the origin of the pharmacophore concept to Ehrlich’s 1909 paper was an extensive review paper published in 1966 by Ariëns, a part of which is quoted below: “The conception that particular moieties of a biologically active compound are of special significance for particular aspects of its action is already old. Ehrlich (1909) differentiated between a haptophoric and a toxophoric group, or a haptophoric and a pharmacophoric group in biologically active compounds.”…”

Section: Introductionmentioning

confidence: 99%

Setting the Record Straight: The Origin of the Pharmacophore Concept

Güner

Bowen

2014

J. Chem. Inf. Model.

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For over a century since the early 1900s, Paul Ehrlich was credited with originating the concept of pharmacophores. This was challenged by John Van Drie in 2007 due to the fact that Ehrlich did not use the word "pharmacophore" in his writings. Van Drie claimed that the attribution of the pharmacophore concept to Ehrlich was due to an erroneous citation made by Ariëns in a 1966 paper, and instead he claimed, Lemont B. Kier developed the pharmacophore concept (in the modern sense, as defined by the IUPAC) during 1967-1971. There are two separate issues that may have triggered this conflict. The first one is the shift in the meaning of pharmacophore from "chemical groups" to patterns of "abstract features" of a molecule that are responsible for a biological effect. Indeed, the original use of the term is different than the current definition proposed by the IUPAC. The term was redefined in 1960 by Schueler, and this modification formed the basis of IUPAC's modern definition. The second issue is the origin of the "concept" of pharmacophore. While Ehrlich's contemporaries have consistently attributed the origin of the concept to him, the issue is further complicated by the fact that Ehrlich did not use the term pharmacophore in his papers. He, instead, referred to the features of a molecule that are responsible for biological effects as toxophores, while his contemporaries were using the term pharmacophore for the same features. In this paper, we resolve any doubts about the origins of the pharmacophore concept. Our research points to Paul Ehrlich's 1898 paper for originating the concept, which identifies peripheral chemical groups in molecules responsible for binding that leads to the subsequent biological effect, and to Schueler's 1960 book that extends the concept to the modern definition where spatial patterns of abstract features of a molecule define the pharmacophore and are ultimately responsible for the biological effect.

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Molecular Pharmacology, a Basis for Drug Design

Cited by 12 publications

References 117 publications

Pharmacophores from Binding Data

Pharmacophores from Binding Data

Directed Drug Delivery

Setting the Record Straight: The Origin of the Pharmacophore Concept

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