Integrated platform promises to accelerate drug discovery process

Many successful drugs have their origins in natural sources such as plants, fungi, and bacteria, but screening natural products to identify potential drugs remains a difficult undertaking.

A new approach using molecular biology, analytical chemistry, and bioinformatics to integrate information from different screening platforms addresses some of the biggest challenges in natural products drug discovery, according to a study published November 30 in Proceedings of the National Academy of Sciences.

A major challenge has been determining the mechanism of action and biological target of a novel bioactive compound. Another central challenge is identifying the molecule or molecules driving biological activity in a complex mixture from nature.

“These two big concepts have been at the heart of our collaborative program, and this paper brings those two questions together in a fully integrated approach,” said corresponding author John MacMillan, professor of chemistry and biochemistry at UC Santa Cruz.

In addition to MacMillan, the collaboration involves Scott Lokey, professor of chemistry and biochemistry and director of the Chemical Screening Center at UC Santa Cruz, Roger Linington at Simon Fraser University in British Columbia, and Michael White at the University of Texas Southwestern Medical Center.

By integrating the results of two completely different screening platforms and combining this with next-generation metabolomics analysis of their natural products libraries, the researchers created a unique and powerful framework for natural product biological characterization. Using this approach to screen a small collection of randomly selected microbial natural product fractions, they were able to identify a known compound (trichostatin A) and confirm its mechanism of action; link a known compound (surugamide) with novel biological activity (cyclin-dependent kinase inhibition); and discover new compounds (parkamycins A and B) with complex biological activity.

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