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1.
J Med Chem ; 65(22): 15416-15432, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36367089

RESUMO

The development of ligands for biological targets is critically dependent on the identification of sites on proteins that bind molecules with high affinity. A set of compounds, called FragLites, can identify such sites, along with the interactions required to gain affinity, by X-ray crystallography. We demonstrate the utility of FragLites in mapping the binding sites of bromodomain proteins BRD4 and ATAD2 and demonstrate that FragLite mapping is comparable to a full fragment screen in identifying ligand binding sites and key interactions. We extend the FragLite set with analogous compounds derived from amino acids (termed PepLites) that mimic the interactions of peptides. The output of the FragLite maps is shown to enable the development of ligands with leadlike potency. This work establishes the use of FragLite and PepLite screening at an early stage in ligand discovery allowing the rapid assessment of tractability of protein targets and informing downstream hit-finding.


Assuntos
Proteínas Nucleares , Fatores de Transcrição , Ligantes , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Domínios Proteicos , Sítios de Ligação , Cristalografia por Raios X , Peptídeos/metabolismo , Ligação Proteica , Proteínas de Ciclo Celular/metabolismo
2.
Org Lett ; 14(10): 2508-11, 2012 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-22545864

RESUMO

Ligand-free cationic Pd(II) catalyst with NaNO3 as an additive is a highly active catalytic system for conjugate additions to sterically hindered γ-substituted cyclohexenones. More challenging γγ- and ßγ-substrates also react well to produce products with quaternary centers in good dr. The conjugate additions occur in a diastereoselective fashion under mild, practical and air-stable conditions, using readily available commercial reagents.

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