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Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra-Terminal Domain.
Adams, Luke A; Wilkinson-White, Lorna E; Gunzburg, Menachem J; Headey, Stephen J; Mohanty, Biswaranjan; Scanlon, Martin J; Capuano, Ben; Mackay, Joel P; Doak, Bradley C.
Afiliación
  • Adams LA; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, VIC, Australia.
  • Wilkinson-White LE; Sydney Analytical Core Research Facility, University of Sydney, Camperdown, NSW 2006, Australia.
  • Gunzburg MJ; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, VIC, Australia.
  • Headey SJ; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, VIC, Australia.
  • Mohanty B; Sydney Analytical Core Research Facility, University of Sydney, Camperdown, NSW 2006, Australia.
  • Scanlon MJ; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, VIC, Australia.
  • Capuano B; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, VIC, Australia.
  • Mackay JP; School of Life and Environmental Sciences, University of Sydney, Camperdown 2006, NSW, Australia.
  • Doak BC; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, VIC, Australia.
J Med Chem ; 66(8): 5859-5872, 2023 04 27.
Article en En | MEDLINE | ID: mdl-37071570
The development of low-affinity fragment hits into higher-affinity leads is a major hurdle in fragment-based drug design. Here, we demonstrate the Rapid Elaboration of Fragments into Leads (REFiL) by applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. After a fragment screen against bromodomain-3 extra-terminal (BRD3-ET) domain, we applied the REFiL workflow, which allowed us to develop a series of ligands that bind to BRD3-ET. With REFiL, we were able to rapidly improve binding affinity > 30-fold. REFiL can be applied readily to a broad range of proteins without the need for a structure, allowing the efficient evolution of low-affinity fragments into higher-affinity leads and chemical probes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diseño de Fármacos / Proteínas Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diseño de Fármacos / Proteínas Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos