8PBO

Deep interactome learning for generative drug design

Summary for 8PBO

• Entry DOI: 10.2210/pdb8pbo/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 3-[2-fluoranyl-4-[3-[2-fluoranyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenoxy]propoxy]phenyl]propanoic acid, GLYCEROL, ... (5 entities in total)
• Functional Keywords: nuclear receptor, complex, ligand, nuclear protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 64040.04

Authors

Hakansson, M.,Focht, D.,Atz, K.,Schneider, G. (deposition date: 2023-06-09, release date: 2024-05-15)

Primary citation

Atz, K.,Cotos, L.,Isert, C.,Hakansson, M.,Focht, D.,Hilleke, M.,Nippa, D.F.,Iff, M.,Ledergerber, J.,Schiebroek, C.C.G.,Romeo, V.,Hiss, J.A.,Merk, D.,Schneider, P.,Kuhn, B.,Grether, U.,Schneider, G.
Prospective de novo drug design with deep interactome learning.
Nat Commun, 15:3408-3408, 2024

PubMed Abstract: De novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties. We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules. This method capitalizes on the unique strengths of both graph neural networks and chemical language models, offering an alternative to the need for application-specific reinforcement, transfer, or few-shot learning. It enables the "zero-shot" construction of compound libraries tailored to possess specific bioactivity, synthesizability, and structural novelty. In order to proactively evaluate the deep interactome learning framework for protein structure-based drug design, potential new ligands targeting the binding site of the human peroxisome proliferator-activated receptor (PPAR) subtype gamma are generated. The top-ranking designs are chemically synthesized and computationally, biophysically, and biochemically characterized. Potent PPAR partial agonists are identified, demonstrating favorable activity and the desired selectivity profiles for both nuclear receptors and off-target interactions. Crystal structure determination of the ligand-receptor complex confirms the anticipated binding mode. This successful outcome positively advocates interactome-based de novo design for application in bioorganic and medicinal chemistry, enabling the creation of innovative bioactive molecules.

PubMed: 38649351
DOI: 10.1038/s41467-024-47613-w

Experimental method

X-RAY DIFFRACTION (1.85 Å)