Mining Natural Products for Macrocycles to Drug Difficult Targets

Over, Bjorn (author): AstraZeneca, Dept Med Chem Res & Early Dev, Early Cardiovasc Renal & Metab, BioPharmaceut R&D, S-43183 Mölndal, Sweden.

Castaldo, Marie (author): AstraZeneca, R&D, Discovery Sci, Discovery Biol, S-43183 Mölndal, Sweden.

Geschwindner, Stefan (author): AstraZeneca, R&D, Discovery Sci, Struct Biophys & Fragment Based Lead Generat, S-43183 Mölndal, Sweden.

Johansson, Patrik (author): AstraZeneca, R&D, Discovery Sci, Struct Biophys & Fragment Based Lead Generat, S-43183 Mölndal, Sweden.

Tyrchan, Christian (author): AstraZeneca, Dept Med Chem Res & Early Dev, BioPharmaceut R&D, Resp & Immunol, S-43183 Mölndal, Sweden.

Wissler, Lisa (author): AstraZeneca, R&D, Discovery Sci, Struct Biophys & Fragment Based Lead Generat, S-43183 Mölndal, Sweden.

Sjo, Peter (author): Drugs Neglected Dis Initiat DNDi, CH-1202 Geneva, Switzerland.

Schiesser, Stefan (author): AstraZeneca, Dept Med Chem Res & Early Dev, BioPharmaceut R&D, Resp & Immunol, S-43183 Mölndal, Sweden.

(creator_code:org_t)

2020-12-18
2021
English.
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:2, s. 1054-1072

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://pubs.acs.org...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Abstract Subject headings

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.

By the author/editor: Begnini, Fabio; Poongavanam, Vas ...; Over, Bjorn; Castaldo, Marie; Geschwindner, St ...; Johansson, Patri ...; show more...; Tyagi, Mohit; Tyrchan, Christi ...; Wissler, Lisa; Sjo, Peter; Schiesser, Stefa ...; Kihlberg, Jan; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medicinal Chemis ...

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