Mining Natural Products for Macrocycles to Drug Difficult Targets.

Fabio Begnini,Lisa Wissler,Vasanthanathan Poongavanam,Jan Kihlberg,Peter Sjö,Mohit Tyagi,Stefan Schiesser,Marie Castaldo,Christian Tyrchan,Björn Over,Patrik Johansson,Stefan Geschwindner

doi:10.1021/acs.jmedchem.0c01569

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.

Highlights

Lead generation is very challenging for targets that have difficultto-drug binding sites,2−4 such as protein−protein interactions (PPIs)
Difficult-to-drug targets that have flat and featureless binding sites are often modulated by macrocyclic drugs, many of which originate from natural products
We mined the macrocycles in the Dictionary of Natural Products to facilitate the identification of novel chemical matter for modulation of difficult-to-drug targets

Summary

■ INTRODUCTION

More than half of all targets predicted to be involved in human disease are considered to be difficult to modulate with traditional small-molecule drugs that obey Lipinski’s rule of 5 (Ro5). Protein−protein interactions (PPIs), proteases, some kinases as well as transferases and isomerases are important examples. These difficult-to-drug targets often have binding sites that are large, featureless, highly lipophilic or highly polar, and/or flexible.− Finding orally bioavailable drugs that reach intracellular difficult-to-drug targets is a daunting task that often requires discovery of ligands in the uncharted chemical space beyond the Ro5 (bRo5). Macrocycles are enriched among oral drugs in the bRo5 space because they offer superior binding to targets that have large and featureless binding sites as compared to traditional small molecules. In addition, macrocyclization may improve plasma stability, cell permeability, and oral absorption. macrocycles are often under-represented in screening collections, limiting their use for lead generation. Protein−protein interactions (PPIs), proteases, some kinases as well as transferases and isomerases are important examples.2,3 These difficult-to-drug targets often have binding sites that are large, featureless, highly lipophilic or highly polar, and/or flexible.− Finding orally bioavailable drugs that reach intracellular difficult-to-drug targets is a daunting task that often requires discovery of ligands in the uncharted chemical space beyond the Ro5 (bRo5).. A collection of lead-like macrocyclic cores would be useful for in silico screening against targets such as PPIs, with subsequent optimization providing novel leads. Such a collection could inspire the design of natural-product-like macrocycle screening libraries. The crystal structure of the complex of Keap and 14 reveals how the uncharged macrocycle 14 binds to the charged binding site of Keap and provides a platform for its further optimization

■ RESULTS

■ DISCUSSION AND CONCLUSIONS

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES