Experimental Design in Synthesis Planning and Structure‐Property Correlations

Austel, Volkhard; Sjöstróm, Michael; Eriksson, Lennart; Hall, Lowell H.; Waterbeemd, van de Han; Costantino, Gabriele; Clementi, Sérgio; Cruciani, Gabriele; Valigi, Roberta

doi:10.1002/9783527615452.ch3

Cited by 18 publications

(8 citation statements)

References 44 publications

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“…It should be noted that a technique referred to as experimental design is usually suggested as a tool for selection of an optimal training set which would allow to study the two aforementionned effects. According to the principles of experimental design one should use in a training set the compounds which are simultaneously varied at several positions.…”

Section: Resultsmentioning

confidence: 99%

A 3D QSAR Study of a Series of HEPT Analogues: The Influence of Conformational Mobility on HIV-1 Reverse Transcriptase Inhibition

et al. 1997

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Quantitative structure-activity relationships (QSAR) have been established for 87 analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), a potent inhibitor of the HIV-1 reverse transcriptase (RT). Of these 87 nonnucleoside RT inhibitors, 9 novel HEPT analogues were used in the study and the others were taken from the literature. The predictive ability of these relationships has been evaluated using a large set of 54 compounds which were not used to derive the activity model. Descriptors related to the conformational changes were found to be an important factor which underlies RT inhibitory activity in the HEPT series. Indeed, the QSAR model provides evidence concerning the conformational transformations the molecules may undergo during the inhibition process. The established relationships are supplementary to the experimental study on the binding of HEPT type inhibitors to RT by Hopkins et al. (J. Med. Chem. 1996, 39, 1589-1600). The present study suggests a quantitative interpretation of the structure-activity relationships which otherwise cannot be explained within the framework of the crystal inhibitor-protein model. This information is pertinent to the further design of new HEPT type RT inhibitors.

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Section: Resultsmentioning

confidence: 99%

A 3D QSAR Study of a Series of HEPT Analogues: The Influence of Conformational Mobility on HIV-1 Reverse Transcriptase Inhibition

et al. 1997

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“…This bin is identified by the property pattern that describes it, i.e., + for lipophilic, for not having a hydrogen bond donor, 0 for not having an overall charge, or, +-0. These bins correspond to the rows of a full factorial design 18 of either three levels or mixed two and three levels.…”

Section: Methodsmentioning

confidence: 99%

Design and Diversity Analysis of Large Combinatorial Libraries Using Cell-Based Methods

Schnur¹

1999

J. Chem. Inf. Comput. Sci.

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Generation of large libraries of small molecules has required a reexamination of the methods chemists use to select their starting materials for synthesis. When a few reagents can be used to generate vast numbers of compounds, selection of an appropriately diverse set of starting materials is important. Since syntheses involve reactions between specific functional groups, it is reasonable to sort reagents by these groups. Then the diversity of the fragments attached to the given reactive functionality may be examined. This diversity may be defined in terms of the biologically relevant properties of a three-dimensional structure. Cell-based methodology can be used to divide reagents into convenient subsets from which representative diverse reagents can be selected for library synthesis. For ECLiPS libraries, analyses of the reagents used in each individual step have proven to be a useful strategy. Further cell-based analyses of the actual libraries in conjunction with biological activity data have shown clustering of actives in the selected diversity spaces.

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“…Selecting a subset of experiments to best represent a much larger potential candidate set falls under the discipline of “experimental design”. Experimental design has been applied to many pharmaceutical problems, including the design of structure−activity relationship (SAR) compound sets, − the optimization of synthetic processes, , the design of calibration standards in analytical chemistry, and the selection of screening subsets from corporate chemical archives . D-optimal design has recently been applied to selecting small numbers of substituents from larger sets of suitable reagents to use in synthetic combinatorial libraries for drug discovery …”

Section: Experimental Designmentioning

confidence: 99%

Beyond Mere Diversity: Tailoring Combinatorial Libraries for Drug Discovery

Martin¹,

Critchlow²

1998

J. Comb. Chem.

157

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Combinatorial library design attempts to choose the best set of substituents for a combinatorial synthetic scheme to maximize the chances of finding a useful compound, such as a drug lead. Initial efforts were focused primarily on maximizing diversity, perhaps allowing some bias by the inclusion of a small, fixed set of pharmacophoric substituents. However, many factors besides diversity impact good library design for drug discovery. A library can be better "tailored" by assigning the candidate substituents to categories such as polar, pharmacophoric, rigid, low molecular weight, and expensive. Stratified sampling by successive steps of D-optimal design generates diverse designs which are also consistent with desirable profiles of these properties. Comparing the diversity scores among design profiles reveals the tradeoffs between diversity, physical property distributions, synthetic difficulty, expense, and pharmacophoric bias. The diversity scores can be calibrated by scoring the best designs from subsets of the candidates made either from specific classes of substituents or by randomly eliminating candidates. This procedure shows how poor random designs are compared even to highly biased optimal designs. Library design requires a synergistic effort between computational and synthetic medicinal chemists, so specialized interactive software has been developed to integrate substructure searching, display, and statistical experimental design to facilitate this interaction for the effective design of well-tailored libraries.

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Experimental Design in Synthesis Planning and Structure‐Property Correlations

Cited by 18 publications

References 44 publications

A 3D QSAR Study of a Series of HEPT Analogues: The Influence of Conformational Mobility on HIV-1 Reverse Transcriptase Inhibition

A 3D QSAR Study of a Series of HEPT Analogues: The Influence of Conformational Mobility on HIV-1 Reverse Transcriptase Inhibition

Design and Diversity Analysis of Large Combinatorial Libraries Using Cell-Based Methods

Beyond Mere Diversity: Tailoring Combinatorial Libraries for Drug Discovery

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