Mining Natural Products for Macrocycles to Drug Difficult Targets

TLDR

Lead generation for difficult‑to‑drug targets with large, featureless, highly lipophilic or highly polar and flexible binding sites is highly challenging. The study proposes using macrocyclic natural product cores as a high‑quality in silico screening library to generate leads for such targets. Two iterative rounds of docking on a curated set of natural‑product‑derived macrocyclic cores produced an uncharged macrocyclic inhibitor of the Keap1‑Nrf2 protein‑protein interaction. The inhibitor displays cellular efficacy, is structurally defined in complex with Keap1, is synthetically accessible, and the work encourages further optimization and broader use of macrocycle cores for in silico lead generation.

Abstract

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.