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 Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN 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 Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN 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 Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, 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 Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN. 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 Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN. 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 Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN 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.
Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
partner:
Reaxense
upacc:
Q14191
UPID:
WRN_HUMAN
Alternative names:
DNA helicase, RecQ-like type 3; RecQ protein-like 2; Werner syndrome protein
Alternative UPACC:
Q14191; A1KYY9
Background:
The Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, also known as Werner syndrome protein, plays a crucial role in maintaining genomic integrity. It exhibits both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity, targeting double-stranded DNA with a 5'-overhang. This protein is pivotal in the dissociation of joint DNA molecules, aiding in homologous recombination, stalled replication forks, and DNA repair processes.
Therapeutic significance:
WRN's involvement in Werner syndrome and Colorectal cancer highlights its therapeutic significance. Werner syndrome, a progeroid syndrome, and Colorectal cancer, a common malignancy, are linked to variants affecting the WRN gene. Understanding WRN's role could lead to novel therapeutic strategies for these conditions.