6Z6A

Keap1 macrocycle complex

Summary for 6Z6A

• Entry DOI: 10.2210/pdb6z6a/pdb
• Descriptor: Kelch-like ECH-associated protein 1, (5S,8R)-8-[[(2S)-1-ethanoylpyrrolidin-2-yl]carbonylamino]-N,N-dimethyl-7,11-bis(oxidanylidene)-10-oxa-3-thia-6-azabicyclo[10.4.0]hexadeca-1(16),12,14-triene-5-carboxamide, SODIUM ION, ... (5 entities in total)
• Functional Keywords: macrocycle, complex, ligase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 64678.75

Authors

Johansson, P. (deposition date: 2020-05-28, release date: 2020-12-30, Last modification date: 2024-11-13)

Primary citation

Begnini, F.,Poongavanam, V.,Over, B.,Castaldo, M.,Geschwindner, S.,Johansson, P.,Tyagi, M.,Tyrchan, C.,Wissler, L.,Sjo, P.,Schiesser, S.,Kihlberg, J.
Mining Natural Products for Macrocycles to Drug Difficult Targets.
J.Med.Chem., 64:1054-1072, 2021

PubMed 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 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 -based lead generation and also inspire the design of future macrocycle screening collections.

PubMed: 33337880
DOI: 10.1021/acs.jmedchem.0c01569

Experimental method

X-RAY DIFFRACTION (2.37 Å)