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2021 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 64, no 2, p. 1054-1072Article in journal (Refereed) Published
Abstract [en]
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 Keapl 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.
Place, publisher, year, edition, pages
American Chemical Society (ACS)AMER CHEMICAL SOC, 2021
Keywords
PROTEIN-PROTEIN INTERACTION; SMALL MOLECULES; KELCH DOMAIN; PREDICTION; DISCOVERY; INHIBITORS; FRAGMENTS; PROGRAM; BIND; RULE
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-437880 (URN)10.1021/acs.jmedchem.0c01569 (DOI)000614306000011 ()33337880 (PubMedID)
Funder
Swedish Research Council, 2016-05160European Commission, 2016-05160
2021-03-222021-03-222024-01-15Bibliographically approved