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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Begnini F,Poongavanam V,Over B,Castaldo M,Geschwindner S,Johansson P,Tyagi M,Tyrchan C,Wissler L,Sjö P,Schiesser S,Kihlberg Jdoi
10.1021/acs.jmedchem.0c01569subject
Has Abstractpub_date
2021-01-28 00:00:00pages
1054-1072issue
2eissn
0022-2623issn
1520-4804journal_volume
64pub_type
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