8ZEM

Crystal Structure of NLRP3 NACHT domain in complex with NP3-1

This is a non-PDB format compatible entry.

Summary for 8ZEM

• Entry DOI: 10.2210/pdb8zem/pdb
• Descriptor: NACHT, LRR and PYD domains-containing protein 3, 1-[5-[2,3-bis(chloranyl)phenyl]-2,3-dihydro-1~{H}-inden-4-yl]-3-[4-(2-oxidanylpropan-2-yl)thiophen-2-yl]sulfonyl-urea, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: nlrp3, inhibitor, np3-1, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 65196.05

Authors

Shi, C.,Liu, Z.M. (deposition date: 2024-05-06, release date: 2024-10-02, Last modification date: 2024-10-23)

Primary citation

Shi, C.,Gao, T.,Lyu, W.,Qiang, B.,Chen, Y.,Chen, Q.,Zhang, L.,Liu, Z.
Deep-Learning-Driven Discovery of SN3-1, a Potent NLRP3 Inhibitor with Therapeutic Potential for Inflammatory Diseases.
J.Med.Chem., 67:17833-17854, 2024

PubMed Abstract: The NLRP3 inflammasome plays a central role in the pathogenesis of various intractable human diseases, making it an urgent target for therapeutic intervention. Here, we report the development of SN3-1, a novel orally potent NLRP3 inhibitor, designed through a lead compound strategy centered on deep-learning-based molecular generative models. Our strategy enables rapid fragment enumeration and takes into account the synthetic accessibility of the compounds, thereby significantly enhancing the optimization of lead compounds and facilitating the discovery of potent inhibitors. X-ray crystallography provided insights into the SN3-1 inhibitory mechanism. SN3-1 has shown a favorable safety profile in both acute and chronic toxicity assessments and exhibits robust pharmacokinetic properties. Furthermore, SN3-1 demonstrated significant therapeutic efficacy in various disease models characterized by NLRP3 activation. This study introduces a potent candidate for developing NLRP3 inhibitors and significantly expands the repertoire of tools available for the discovery of novel inhibitors.

PubMed: 39302813
DOI: 10.1021/acs.jmedchem.4c01857

Experimental method

X-RAY DIFFRACTION (3.32 Å)