Combining the power of synthetic chemistry with some advanced screening technologies, the new approach could eventually expand by millions the 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 the foundation of current drug discovery efforts.
The study, led by Scripps Research Associate Professor Glenn Micalizio, was published Nov. 20, 2011, in an advanced online edition of the journal Nature Chemistry.
To frame the significance of this advance, Micalizio explains that high-throughput screening is an important component of modern drug discovery. In high-throughput screening, diverse collections of molecules are evaluated en masse 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. Modern screening centers maintain a relatively static collection of molecules, the majority of which are commercially available materials that have structures unrelated to natural products -- molecules that are appreciated as validated leads for drug development.
"This divergence in structure between natural products and commercially available synthetics lies at the heart of our inquiry," said Micalizio. "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 centers?"
To expand the compounds available for investigation, the scientists embraced an approach to structural diversity that mimics nature's engine for the discovery of molecules with biological function. This process, termed "oligomerization," is a modular means of assembling structures (akin to the way that letters are used in a sequence to provide words with meaning) where a small collection of monomeric units can deliver a vast collection of oligomeric products of varying length, structure, and function (like the diversity of words presented in a dictionary).
Coupling this technique with a synthetic design aimed at generating molecules that boast molecular features inspired by the structures of bioactive natural products (specifically, polyketide-derived natural products, which include erythromycin, FK-506, and epothilone), the scientists established a new chemical platform for the discovery of potential therapeutics.
Micalizio points out: "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 crux of 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."
"It is the stability associated with the shape of these new compounds that lies at the heart of the practical advance," he continued. "The unique features of this science now make possible the ability to synthesize large collections of diverse natural product-inspired structures that have predictable and stable three-dimensional shapes."
Micalizio said that the science described represents a first step toward revolutionizing discovery at the interface of chemistry, biology, and medicine by embracing nature's strategy for molecular discovery. Coupling this type of advance with modern screening technology that can handle the evaluation of large compound collections at low cost (such as work by Scripps Florida Professor Thomas Kodadek, a co-author of the new study), can dramatically enhance the future of pharmaceutically relevant science.
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 of Scripps Research. In addition to Micalizio and Kodadek, other authors include Mohosin Sarkar, Michael J. Chalmers, and Kimberly Mendes.
The study was supported by the Fidelity Biosciences Research Initiative, The State of Florida (The Florida Funding Corporation), and the National Institutes of Health.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see http://www.scripps.edu.
Mika Ono | EurekAlert!
If Machines Could Smell ...
19.07.2019 | Fraunhofer-Institut für Produktionstechnik und Automatisierung IPA
Algae-killing viruses spur nutrient recycling in oceans
18.07.2019 | Rutgers University
Adjusting the thermal conductivity of materials is one of the challenges nanoscience is currently facing. Together with colleagues from the Netherlands and Spain, researchers from the University of Basel have shown that the atomic vibrations that determine heat generation in nanowires can be controlled through the arrangement of atoms alone. The scientists will publish the results shortly in the journal Nano Letters.
In the electronics and computer industry, components are becoming ever smaller and more powerful. However, there are problems with the heat generation. It is...
Scientists have visualised the electronic structure in a microelectronic device for the first time, opening up opportunities for finely-tuned high performance electronic devices.
Physicists from the University of Warwick and the University of Washington have developed a technique to measure the energy and momentum of electrons in...
Scientists at the University Würzburg and University Hospital of Würzburg found that megakaryocytes act as “bouncers” and thus modulate bone marrow niche properties and cell migration dynamics. The study was published in July in the Journal “Haematologica”.
Hematopoiesis is the process of forming blood cells, which occurs predominantly in the bone marrow. The bone marrow produces all types of blood cells: red...
For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.
Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...
An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".
The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...
24.06.2019 | Event News
29.04.2019 | Event News
17.04.2019 | Event News
19.07.2019 | Physics and Astronomy
19.07.2019 | Physics and Astronomy
19.07.2019 | Earth Sciences