2. Academic Validation
  3. A Complementarity-Based Approach to De Novo Binder Design

A Complementarity-Based Approach to De Novo Binder Design

  • Adv Sci (Weinh). 2025 Sep;12(33):e02015. doi: 10.1002/advs.202502015.
Kateryna Maksymenko 1 2,  Valeriia Hatskovska 1 3,  Murray Coles 1,  Narges Aghaallaei 3 4,  Natalia Pashkovskaia 5,  Natalia Borbarán-Bravo 3,  Matteo Pilz 6 7,  Philip Bucher 8 9,  Mareike Volz 5,  Joana Pereira 1 10 11,  Marcus D Hartmann 1 12,  Ghazaleh Tabatabai 8 13,  Judith Feucht 8 9,  Stefan Liebau 5,  Patrick Müller 2 14,  Andrei N Lupas 1,  Julia Skokowa 3,  Mohammad ElGamacy 1 2 3
Affiliations

Affiliations

  • 1 Department of Protein Evolution, Max Planck Institute for Biology, 72076, Tübingen, Germany.
  • 2 Friedrich Miescher Laboratory of the Max Planck Society, 72076, Tübingen, Germany.
  • 3 Division of Translational Oncology, University Hospital Tübingen, 72076, Tübingen, Germany.
  • 4 Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, 1090, Austria.
  • 5 Institute of Neuroanatomy and Developmental Biology, Eberhard Karls University Tübingen, 72074, Tübingen, Germany.
  • 6 Applied Bioinformatics, Department of Computer Science, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
  • 7 Institute for Bioinformatics and Medical Informatics, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
  • 8 Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
  • 9 Department of Pediatric Hematology and Oncology, Eberhard Karls University Tübingen, University Children's Hospital, 72076, Tübingen, Germany.
  • 10 VIB Center for AI and Computational Biology (VIB.AI), VIB, Leuven, 3000, Belgium.
  • 11 Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium.
  • 12 Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
  • 13 Department of Neurology and Neuro-Oncology, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
  • 14 Department of Biology, University of Konstanz, 78457, Konstanz, Germany.
PMID: 40686280 DOI: 10.1002/advs.202502015
Abstract

De novo design of Binders capable of targeting arbitrarily selected epitopes remains a substantial challenge. Here, a generalizable computational strategy is presented to design site-specific protein Binders, obviating steps of extensive empirical optimization or in vitro screening. The dock-and-design pipeline retrieves complementary scaffolds from a protein structure database to a given query epitope, where the scaffold is mutated to carve a binding site de novo. The docking step utilizes a novel fingerprint that greatly simplifies and accelerates the surface complementarity evaluation. As proof-of-concept, we designed protein Binders to target three distinct epitopes on two different oncogenic targets; vascular endothelial growth factor (VEGF) and interleukin-7 receptor-α (IL-7Rα). Experimental characterization of only 24 candidates identified nanomolar Binders against each of the target epitopes, where the Binders belonged to five different folds. Several designs were active in vitro. Moreover, anti-VEGF designs showed tumor-inhibiting activity in vivo, highlighting their therapeutic potential.

Keywords

de novo binder design; IL‐7R binders; VEGF inhibitors; complementarity evaluation; protein‐protein docking.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-P9906
    ≥99.0%, VEGF Blocking Antibody