Mining Natural Products for Macrocycles to Drug Difficult Targets

Lead
generation for difficult-to-drug targets that have large,
featureless, and highly lipophilic or highly polar and/or flexible
binding sites is highly challenging. Here, we describe how cores of
macrocyclic natural products can serve as a high-quality in
silico screening library that provides leads for difficult-to-drug
targets. Two iterative rounds of docking of a carefully selected set
of natural-product-derived cores led to the discovery of an uncharged
macrocyclic inhibitor of the Keap1-Nrf2 protein–protein interaction,
a particularly challenging target due to its highly polar binding
site. The inhibitor displays cellular efficacy and is well-positioned
for further optimization based on the structure of its complex with
Keap1 and synthetic access. We believe that our work will spur interest
in using macrocyclic cores for in silico-based lead
generation and also inspire the design of future macrocycle screening
collections.