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Expansive discovery of chemically diverse structured macrocyclic oligoamides.
Salveson, Patrick J; Moyer, Adam P; Said, Meerit Y; GÓ§kçe, Gizem; Li, Xinting; Kang, Alex; Nguyen, Hannah; Bera, Asim K; Levine, Paul M; Bhardwaj, Gaurav; Baker, David.
Afiliación
  • Salveson PJ; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Moyer AP; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Said MY; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • GÓ§kçe G; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Li X; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Kang A; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Nguyen H; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Bera AK; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
  • Levine PM; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Bhardwaj G; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Baker D; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Science ; 384(6694): 420-428, 2024 Apr 26.
Article en En | MEDLINE | ID: mdl-38662830
ABSTRACT
Small macrocycles with four or fewer amino acids are among the most potent natural products known, but there is currently no way to systematically generate such compounds. We describe a computational method for identifying ordered macrocycles composed of alpha, beta, gamma, and 17 other amino acid backbone chemistries, which we used to predict 14.9 million closed cycles composed of >42,000 monomer combinations. We chemically synthesized 18 macrocycles predicted to adopt single low-energy states and determined their x-ray or nuclear magnetic resonance structures; 15 of these were very close to the design models. We illustrate the therapeutic potential of these macrocycle designs by developing selective inhibitors of three protein targets of current interest. By opening up a vast space of readily synthesizable drug-like macrocycles, our results should considerably enhance structure-based drug design.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos Cíclicos / Productos Biológicos / Diseño de Fármacos / Amidas / Aminoácidos Idioma: En Revista: Science Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos Cíclicos / Productos Biológicos / Diseño de Fármacos / Amidas / Aminoácidos Idioma: En Revista: Science Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos