Catalyst-Directed Divergent Catalytic Approaches to Expand Structural and Functional Scaffold Diversity via Metallo-Enolcarbene Intermediates

Synthesis and Screening of A DNA-Encoded Library of Non-Peptidic Macrocycles

10.26434/chemrxiv.13490151.v1 ◽

2020 ◽

Author(s):

Eric Koesema ◽

Animesh Roy ◽

Nicholas G. Paciaroni ◽

Thomas Kodadek

Keyword(s):

Solid Phase Synthesis ◽

Solid Phase ◽

Cell Permeability ◽

Phase Synthesis ◽

Protein Ligands ◽

High Affinity ◽

Scaffold Diversity

There is considerable interest in the development of libraries of non-peptidic macrocycles as a source of ligands for difficult targets. We report here the solid-phase synthesis of a DNA-encoded library of several hundred thousand thioether-linked macrocycles. The library was designed to be highly diverse with respect to backbone scaffold diversity and to minimize the number of amide N-H bonds, which compromise cell permeability. The utility of the library as a source of protein ligands is demonstrated through the isolation of compounds that bind streptavidin, a model target, with high affinity.

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Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

Diversity Oriented Synthesis ◽

10.2478/dos-2013-0001 ◽

2013 ◽

Vol 1 (1) ◽

Cited By ~ 5

Author(s):

Warren R.J.D. Galloway ◽

David R. Spring

Keyword(s):

Small Molecule ◽

Structural Diversity ◽

Library Size ◽

Diversity Oriented Synthesis ◽

Biological Targets ◽

Small Molecule Screening ◽

Chemistry Research ◽

Large Numbers ◽

Small Molecule Libraries ◽

Scaffold Diversity

AbstractMedicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

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iVS analysis to evaluate the impact of scaffold diversity in the binding to cellular targets relevant in cancer

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.1080/14756366.2018.1518960 ◽

2018 ◽

Vol 34 (1) ◽

pp. 44-50 ◽

Cited By ~ 2

Author(s):

Agostino Cilibrizzi ◽

Giuseppe Floresta ◽

Vincenzo Abbate ◽

Maria Paola Giovannoni

Keyword(s):

Cellular Targets ◽

Scaffold Diversity ◽

The Impact

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ScaffoldGraph: an open-source library for the generation and analysis of molecular scaffold networks and scaffold trees

Bioinformatics ◽

10.1093/bioinformatics/btaa219 ◽

2020 ◽

Vol 36 (12) ◽

pp. 3930-3931 ◽

Cited By ~ 1

Author(s):

Oliver B Scott ◽

A W Edith Chan

Keyword(s):

Open Source ◽

High Throughput Screening ◽

Chemical Space ◽

Diversity Analysis ◽

Graph Analysis ◽

Command Line ◽

Molecular Scaffold ◽

Large Sets ◽

Command Line Tool ◽

Scaffold Diversity

Abstract Summary ScaffoldGraph (SG) is an open-source Python library and command-line tool for the generation and analysis of molecular scaffold networks and trees, with the capability of processing large sets of input molecules. With the increase in high-throughput screening data, scaffold graphs have proven useful for the navigation and analysis of chemical space, being used for visualization, clustering, scaffold-diversity analysis and active-series identification. Built on RDKit and NetworkX, SG integrates scaffold graph analysis into the growing scientific/cheminformatics Python stack, increasing the flexibility and extendibility of the tool compared to existing software. Availability and implementation SG is freely available and released under the MIT licence at https://github.com/UCLCheminformatics/ScaffoldGraph.

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