CCB Seminar: Greg Bowman (UPenn)

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Cracking “undruggable” proteins with cryptic pockets

Abstract

Many proteins are thought to be difficult drug targets, or even outright “undruggable,” because their structures lack pockets that appear amenable to drug discovery or their functional sites are conserved, making specificity difficult to achieve. Considering protein dynamics could alleviate these concerns in many cases, greatly expanding the druggable proteome. For example, ‘cryptic’ pockets that are absent in known structures of proteins but form due to protein dynamics could provide a means to target proteins thought to lack druggable pockets. Furthermore, allosteric sites, whether cryptic or not, could provide a means to specifically target subsets of proteins with shared functional sites. However, it has been challenging to assess or exploit these dynamical features due to the inherent difficulty in identifying them. Here, I will discuss progress from my lab on combining biophysical experiments, adaptive sampling simulations, and machine learning to identify and target cryptic pockets and allostery.

*This event is supported by, and is part of, the Albrecht Lecture Series