Development small molecules drug discovery

Development of small molecules for drug discovery

1:13 AM, 22nd November 2011
Development of small molecules for drug discovery
Professor Glenn Micalizio, Research Associate, Scripps.


JUPITER, US: Scripps Research Institute has created a new class of small molecules with potential to serve as a rich foundation for drug discovery. The study is led by Professor Glenn Micalizio, Research Associate, Scripps. Combining the power of synthetic chemistry with some advanced screening technologies, the new approach could eventually expand by millions number of provocative synthetic compounds available to explore as potential drug candidates. This approach overcomes substantial molecular limitations associated with state-of-the-art approaches in small molecule synthesis and screening, which often serve as foundation of current drug discovery efforts.

To frame the significance of this advance, Micalizio explained that high-throughput screening is an important component of modern drug discovery. In high-throughput screening, diverse collections of molecules are evaluated for potential function in a biological area of interest. In this process, success is critically dependent on the composition of the molecular collections under evaluation. “This divergence in structure between natural products and commercially available synthetics lies at the heart of our inquiry. And why should we limit discovery of therapeutic leads to compound collections that are influenced by concerns relating to commercial availability and compatibility with an artificial set of constraints associated with the structure of modern screening centres?,” said Micalizio.

To expand the compounds available for investigation, scientists embraced an approach to structural diversity that mimics nature’s engine for discovery of molecules with biological function. This process, termed “oligomerization,” is a modular means of assembling structure where a small collection of monomeric units can deliver a vast collection of oligomeric products of varying length, structure and function.

The scientists have established a new chemical platform for discovery of potential therapeutics by coupling this technique with a synthetic design aimed at generating molecules that boast molecular features inspired by the structures of bioactive natural products. “The importance of oligomerization to drive discovery is well appreciated in chemistry and biology, yet a means to realize this process as an entry to small molecule natural product-inspired structures has remained elusive. The problem is related to challenges associated with the control of shape for each member of a complex oligomer collection-the central molecular feature that defines biological function,” said Micalizio.

The potential of this vision was highlighted in the new study, in which a 160,000 member compound collection was employed to discover the first non-covalent small molecule ligand to the DNA binding domain of p53 - an important transcription factor that regulates a variety of genes involved in cell cycle control and cell death.

The first author of the study, “A biomimetic polyketide-inspired approach to small-molecule ligand discovery,” is Claudio Aquino, Scripps Research. In addition to Micalizio and Kodadek, other authors include Mohosin Sarkar, Michael J Chalmers, and Kimberly Mendes.

© The Scripps Research Institute News




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