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journal article·2025-09Open access

A Complementarity‐Based Approach to De Novo Binder Design

Kateryna Maksymenko, Valeriia Hatskovska, Murray Coles, Narges Aghaallaei, Natalia Pashkovskaia, Natalia Borbarán‐Bravo, Matteo Pilz, Philip Bucher, Mareike Volz, Joana Pereira, Marcus D. Hartmann, Ghazaleh Tabatabai, Judith Feucht, Stefan Liebau, Patrick Müller, Andrei N. Lupas, Julia Skokowa, Mohammad ElGamacy

Advanced Science· Volume 12· Issue 33
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Source abstract

Abstract

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.
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Research context

Nanomaterials

OpenAlex topics: Manufacturing Process and Optimization · Injection Molding Process and Properties · Innovations in Concrete and Construction Materials

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Protein Evolution Max Planck Institute for Biology 72076 Tübingen Germany

Friedrich Miescher Laboratory of the Max Planck Society 72076 Tübingen Germany

Division of Translational Oncology University Hospital Tübingen 72076 Tübingen Germany

Ludwig Boltzmann Institute for Hematology and Oncology Medical University of Vienna Vienna 1090 Austria

Institute of Neuroanatomy and Developmental Biology Eberhard Karls University Tübingen 72074 Tübingen Germany

Applied Bioinformatics Department of Computer Science Eberhard Karls University Tübingen 72076 Tübingen Germany

Institute for Bioinformatics and Medical Informatics Eberhard Karls University Tübingen 72076 Tübingen Germany

Cluster of Excellence iFIT (EXC2180) “Image‐guided and Functionally Instructed Tumor Therapies” Eberhard Karls University Tübingen 72076 Tübingen Germany

Department of Pediatric Hematology and Oncology Eberhard Karls University Tübingen University Children's Hospital 72076 Tübingen Germany

VIB Center for AI and Computational Biology (VIB.AI), VIB Leuven 3000 Belgium

Department of Cellular and Molecular Medicine KU Leuven Leuven 3000 Belgium

Interfaculty Institute of Biochemistry Eberhard Karls University Tübingen 72076 Tübingen Germany

Department of Neurology and Neuro‐Oncology, University Hospital Tübingen, Hertie Institute for Clinical Brain Research Eberhard Karls University Tübingen 72076 Tübingen Germany

Department of Biology University of Konstanz 78457 Konstanz Germany

Funding

HORIZON EUROPE European Research Council · Deutsche Forschungsgemeinschaft · José Carreras Leukämie-Stiftung · Max-Planck-Gesellschaft

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