Small Molecules Discovery

In this chapter, we will introduce an exciting class of natural product biosynthetic enzymes, the modular synthases, as well as their associated enzyme partners. We will discuss the use of metabolic engineering as a tool for small-molecule discovery and development, both through directed fermentation and combinatorial biosynthesis. In addition, we will review six classes of partner enzymes involved in the modification of polyketide (PK) and nonribosomal peptide (NRP) natural products. We believe that these enzymatic transformations hold great opportunities for synthetic chemists and will serve as the foundation for a new trend in both discovery and process chemistry. 

Changes induced by SNPs (or other mutations) in the protein targets of drugs may result in the medicine being ineffective. In this case, the relevant disease may remain untreated, or else an expensive drug discovery effort will have to be undertaken to identify new molecules that are able to affect the mutant protein. Given that most current small molecule discovery strategies rely on expensive... 

Figure 16.1 Dichloromethane use at Pfizer small-molecule discovery sites (Groton, CT La Jolla, CA Sandwich, UK).

The PK/PD properties of ASOs provide a framework for rapid drug development. Challenges to the promise of antisense therapeutics are not unlike those for any other new chemical entity, and they include proper application of the pharmacokinetic properties in order to select both target and delivery methods. The profound difference from the situation of small molecule discovery is the relative predictability of the pharmacokinetics, independent of target selection. 

More recent efforts now indicate that this activity is far more complex than the targeting of this single event, as different phenotypic responses readily occur across a panel of cell lines. While at this time it is difficult to determine if this discovery provides a drug target, it has become clear that development of systems that target intermediate filaments and their cytokeratin structures offers a new realm for small molecule discovery. 

Lazo JS, Brady LS, Dingledine R. Building a pharmacological lexicon small molecule discovery in academia. Mol. Pharmacol. 2007 72 1-7. 

A variety of methods have been employed to co-crystallize biological molecules with small molecules. Discovery of crystallization conditions is still an often tedious task, so newer methods for screening crystallization conditions for proteins include the use of semi-automated robots. 

Merlot C, Domine D, Church DJ. Eragment analysis in small molecule discovery. Curr Opin Drug Discov Devel 2002 5(3) 391-399. 

Since MASPIT is a simple binding assay, it could also be used potentially to screen small molecule libraries for compounds that interfere with or compete for binding of a known molecule with its target protein. Therefore, MASPIT provides an opportunity for small molecule discovery that is not possible with Y3H (due to the less favorable permeability of yeast cells to small molecules). 

Small molecule discovery chemical libraries (MW < 1500 Da) play an essential role in chemical biology and drug discovery. Specifically, libraries of 10-100 members derived from a core scaffold by adding various appendages can offer a very effective... 

By virtue of its well-established nature in a number of industries, scalability, and excellent process control, melt extrusion meets the needs of both biotechnology and small molecule discovery pipelines. Combining this with an ever-expanding compositional knowledge for the technology, melt extrusion will make a clear difference in the future of drug delivery. 

MacRae, C. A. and Peterson, R. T. 2003. Zebra fish-based small molecule discovery. Chem. Biol 10(10) 901-8. 

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