De novo design of drug-binding proteins with predictable binding energy and specificity

• DOI: 10.1126/science.adl5364
• Publication Date: 2024-04-04T17:58:54Z
• Authors: Lei Lu; Xuxu Gou; Sophia K. Tan; Samuel I. Mann; Hyunjun Yang; Xiaofang Zhong; Dimitrios Gazgalis; Jesús Valdiviezo; Hyunil Jo; Yibing Wu; Morgan E. Diolaiti; Alan Ashworth; Nicholas F. Polizzi; William F. DeGrado
• Keywords: 0301 basic medicine; 0303 health sciences; Design; Binding Sites; Pharmacophore; General Science & Technology; Proteins; Bioengineering; Molecular Dynamics Simulation; Poly(ADP-ribose) Polymerase Inhibitors; 540; Ligands; Protein Engineering; Article; Medicinal and Biomolecular Chemistry; Networking and Information Technology R&D (NITRD); Built Environment and Design; 5.1 Pharmaceuticals; Chemical Sciences; Humans; Patient Safety; Biotechnology; Protein Binding

The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening optimization after computational design. We developed a procedure to protein that recognizes common pharmacophore in series poly(ADP-ribose) polymerase-1 inhibitors. One three designed bound different inhibitors with affinities ranging from <5 nM low micromolar. X-ray crystal structures confirmed the accuracy protein-drug interactions. Molecular dynamics simulations informed role water binding. Binding free energy calculations performed directly on models were excellent agreement experimentally measured affinities. conclude tuned interaction energies is feasible entirely computation.