Identification of 3D Scaffolds Embedded in Natural Products and Synthesis of Focused Libraries
Author(s)
Primary Supervisor
Quinn, Ronald
Other Supervisors
Campitelli, Marc
Pouwer, Rebecca
Year published
2017
Metadata
Show full item recordAbstract
The ever-increasing demand for new drugs drives the need to explore new areas of biologically-relevant chemical space. Drug targets, largely the active sites of proteins, have three-dimensional shape. However, chiefly for reasons of synthetic tractability, the screening libraries that are extensively used for high throughput screening (HTS) drug discovery are mostly composed of flat aromatic and heteroaromatic compounds.1 This has resulted in a trend towards flatness in drug candidates, limiting the possibilities in the navigation of three-dimensional biological space. A variety of approaches, such as diversity-oriented ...
View more >The ever-increasing demand for new drugs drives the need to explore new areas of biologically-relevant chemical space. Drug targets, largely the active sites of proteins, have three-dimensional shape. However, chiefly for reasons of synthetic tractability, the screening libraries that are extensively used for high throughput screening (HTS) drug discovery are mostly composed of flat aromatic and heteroaromatic compounds.1 This has resulted in a trend towards flatness in drug candidates, limiting the possibilities in the navigation of three-dimensional biological space. A variety of approaches, such as diversity-oriented synthesis (DOS),2, 3 target-oriented synthesis (TOS),2, 4 function-oriented synthesis (FOS),5 and biology-oriented synthesis (BIOS)6, 7 have emerged to address this issue. Natural products are a source of therapeutically useful compounds with high success rates in drug discovery.8 They tend to be highly saturated, and therefore non-flat, molecules with chiral centres. These features of natural products arise from interaction with the active sites of proteins involved in biosynthetic pathways. Inspired by natural products, we sought to identify three-dimensional (3D) molecular scaffolds embedded in natural products with the aim of producing focused synthetic libraries that explore new biological profiles.
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View more >The ever-increasing demand for new drugs drives the need to explore new areas of biologically-relevant chemical space. Drug targets, largely the active sites of proteins, have three-dimensional shape. However, chiefly for reasons of synthetic tractability, the screening libraries that are extensively used for high throughput screening (HTS) drug discovery are mostly composed of flat aromatic and heteroaromatic compounds.1 This has resulted in a trend towards flatness in drug candidates, limiting the possibilities in the navigation of three-dimensional biological space. A variety of approaches, such as diversity-oriented synthesis (DOS),2, 3 target-oriented synthesis (TOS),2, 4 function-oriented synthesis (FOS),5 and biology-oriented synthesis (BIOS)6, 7 have emerged to address this issue. Natural products are a source of therapeutically useful compounds with high success rates in drug discovery.8 They tend to be highly saturated, and therefore non-flat, molecules with chiral centres. These features of natural products arise from interaction with the active sites of proteins involved in biosynthetic pathways. Inspired by natural products, we sought to identify three-dimensional (3D) molecular scaffolds embedded in natural products with the aim of producing focused synthetic libraries that explore new biological profiles.
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Thesis Type
Thesis (PhD Doctorate)
Degree Program
Doctor of Philosophy (PhD)
School
School of Natural Sciences
Copyright Statement
The author owns the copyright in this thesis, unless stated otherwise.
Subject
Drug discovery
Heteroaromatic compounds
Diversity-oriented synthesis
Target-oriented synthesis (TOS)
Function-oriented synthesis (FOS)
Biology-oriented synthesis (BIOS)
Molecular scaffolds
Natural products