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De novo design of drug-binding proteins with predictable binding energy and specificity.
Lu, Lei; Gou, Xuxu; Tan, Sophia K; Mann, Samuel I; Yang, Hyunjun; Zhong, Xiaofang; Gazgalis, Dimitrios; Valdiviezo, Jesús; Jo, Hyunil; Wu, Yibing; Diolaiti, Morgan E; Ashworth, Alan; Polizzi, Nicholas F; DeGrado, William F.
Afiliación
  • Lu L; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Gou X; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA.
  • Tan SK; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Mann SI; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Yang H; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Zhong X; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Gazgalis D; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA.
  • Valdiviezo J; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
  • Jo H; Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Wu Y; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
  • Diolaiti ME; Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Ashworth A; Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Polizzi NF; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
  • DeGrado WF; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
bioRxiv ; 2023 Dec 23.
Article en En | MEDLINE | ID: mdl-38187746
ABSTRACT
The de novo design of small-molecule-binding proteins has seen exciting recent progress; however, the ability to achieve exquisite affinity for binding small molecules while tuning specificity has not yet been demonstrated directly from computation. Here, we develop a computational procedure that results in the highest affinity binders to date with predetermined relative affinities, targeting a series of PARP1 inhibitors. Two of four designed proteins bound with affinities ranging from < 5 nM to low µM, in a predictable manner. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free-energy calculations performed directly on the designed models are in excellent agreement with the experimentally measured affinities, suggesting that the de novo design of small-molecule-binding proteins with tuned interaction energies is now feasible entirely from computation. We expect these methods to open many opportunities in biomedicine, including rapid sensor development, antidote design, and drug delivery vehicles.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: BioRxiv Año: 2023 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 Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos