8UXS

KLHDC2 ubiquitin ligase in complex with a novel small-molecule

Summary for 8UXS

• Entry DOI: 10.2210/pdb8uxs/pdb
• Descriptor: Kelch domain-containing protein 2, {4-[(2-{[(4-tert-butylphenyl)methyl]sulfanyl}acetamido)methyl]-1H-1,2,3-triazol-1-yl}acetic acid (3 entities in total)
• Functional Keywords: kelch repeat, beta-propeller, small-molecule, complex, substrate receptor, e3, ubiquitin ligase, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 78748.32

Authors

Rusnac, D.V.,Zheng, N. (deposition date: 2023-11-10, release date: 2024-07-10, Last modification date: 2025-01-22)

Primary citation

Zhou, G.,Rusnac, D.V.,Park, H.,Canzani, D.,Nguyen, H.M.,Stewart, L.,Bush, M.F.,Nguyen, P.T.,Wulff, H.,Yarov-Yarovoy, V.,Zheng, N.,DiMaio, F.
An artificial intelligence accelerated virtual screening platform for drug discovery.
Nat Commun, 15:7761-7761, 2024

PubMed Abstract: Structure-based virtual screening is a key tool in early drug discovery, with growing interest in the screening of multi-billion chemical compound libraries. However, the success of virtual screening crucially depends on the accuracy of the binding pose and binding affinity predicted by computational docking. Here we develop a highly accurate structure-based virtual screen method, RosettaVS, for predicting docking poses and binding affinities. Our approach outperforms other state-of-the-art methods on a wide range of benchmarks, partially due to our ability to model receptor flexibility. We incorporate this into a new open-source artificial intelligence accelerated virtual screening platform for drug discovery. Using this platform, we screen multi-billion compound libraries against two unrelated targets, a ubiquitin ligase target KLHDC2 and the human voltage-gated sodium channel Na1.7. For both targets, we discover hit compounds, including seven hits (14% hit rate) to KLHDC2 and four hits (44% hit rate) to Na1.7, all with single digit micromolar binding affinities. Screening in both cases is completed in less than seven days. Finally, a high resolution X-ray crystallographic structure validates the predicted docking pose for the KLHDC2 ligand complex, demonstrating the effectiveness of our method in lead discovery.

PubMed: 39237523
DOI: 10.1038/s41467-024-52061-7

Experimental method

X-RAY DIFFRACTION (2 Å)