AI-ACCELERATED DRUG DISCOVERY
Available from Reaxense
This protein is integrated into the Receptor.AI ecosystem as a prospective target with high therapeutic potential. We performed a comprehensive characterization of Histone-lysine N-methyltransferase EZH2 including:
1. LLM-powered literature research
Our custom-tailored LLM extracted and formalized all relevant information about the protein from a large set of structured and unstructured data sources and stored it in the form of a Knowledge Graph. This comprehensive analysis allowed us to gain insight into Histone-lysine N-methyltransferase EZH2 therapeutic significance, existing small molecule ligands, relevant off-targets, and protein-protein interactions.
Fig. 1. Preliminary target research workflow
2. AI-Driven Conformational Ensemble Generation
Starting from the initial protein structure, we employed advanced AI algorithms to predict alternative functional states of Histone-lysine N-methyltransferase EZH2, including large-scale conformational changes along "soft" collective coordinates. Through molecular simulations with AI-enhanced sampling and trajectory clustering, we explored the broad conformational space of the protein and identified its representative structures. Utilizing diffusion-based AI models and active learning AutoML, we generated a statistically robust ensemble of equilibrium protein conformations that capture the receptor's full dynamic behavior, providing a robust foundation for accurate structure-based drug design.
Fig. 2. AI-powered molecular dynamics simulations workflow
3. Binding pockets identification and characterization
We employed the AI-based pocket prediction module to discover orthosteric, allosteric, hidden, and cryptic binding pockets on the protein’s surface. Our technique integrates the LLM-driven literature search and structure-aware ensemble-based pocket detection algorithm that utilizes previously established protein dynamics. Tentative pockets are then subject to AI scoring and ranking with simultaneous detection of false positives. In the final step, the AI model assesses the druggability of each pocket enabling a comprehensive selection of the most promising pockets for further targeting.
Fig. 3. AI-based binding pocket detection workflow
4. AI-Powered Virtual Screening
Our ecosystem is equipped to perform AI-driven virtual screening on Histone-lysine N-methyltransferase EZH2. With access to a vast chemical space and cutting-edge AI docking algorithms, we can rapidly and reliably predict the most promising, novel, diverse, potent, and safe small molecule ligands of Histone-lysine N-methyltransferase EZH2. This approach allows us to achieve an excellent hit rate and to identify compounds ready for advanced lead discovery and optimization.
Fig. 4. The screening workflow of Receptor.AI
Receptor.AI, in partnership with Reaxense, developed a next-generation technology for on-demand focused library design to enable extensive target exploration.
The focused library for Histone-lysine N-methyltransferase EZH2 includes a list of the most effective modulators, each annotated with 38 ADME-Tox and 32 physicochemical and drug-likeness parameters. Furthermore, each compound is shown with its optimal docking poses, affinity scores, and activity scores, offering a detailed summary.
Histone-lysine N-methyltransferase EZH2
partner:
Reaxense
upacc:
Q15910
UPID:
EZH2_HUMAN
Alternative names:
ENX-1; Enhancer of zeste homolog 2; Lysine N-methyltransferase 6
Alternative UPACC:
Q15910; B2RAQ1; B3KS30; B7Z1D6; B7Z7L6; Q15755; Q75MG3; Q92857; Q96FI6
Background:
Histone-lysine N-methyltransferase EZH2, also known as ENX-1 and Enhancer of zeste homolog 2, plays a pivotal role in gene expression regulation through histone methylation. As a key component of the PRC2/EED-EZH2 complex, it specifically methylates 'Lys-27' of histone H3, influencing transcriptional repression. Its activity varies with the methylation state of H3K27, showing a preference for substrates with less methylation. EZH2's function is crucial in maintaining embryonic stem cell identity and differentiation, highlighting its importance in cellular development and epigenetic regulation.
Therapeutic significance:
EZH2's involvement in Weaver syndrome, characterized by accelerated growth and distinctive craniofacial features, underscores its clinical relevance. The disease's association with EZH2 gene variants opens avenues for targeted therapeutic strategies, emphasizing the protein's potential as a biomarker and therapeutic target in genetic disorders.
