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 ADP-ribosylhydrolase ARH3 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 ADP-ribosylhydrolase ARH3 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 ADP-ribosylhydrolase ARH3, 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 ADP-ribosylhydrolase ARH3. 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 ADP-ribosylhydrolase ARH3. 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 ADP-ribosylhydrolase ARH3 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.
ADP-ribosylhydrolase ARH3
partner:
Reaxense
upacc:
Q9NX46
UPID:
ADPRS_HUMAN
Alternative names:
ADP-ribose glycohydrolase ARH3; ADP-ribosylhydrolase 3; O-acetyl-ADP-ribose deacetylase ARH3; Poly(ADP-ribose) glycohydrolase ARH3; [Protein ADP-ribosylarginine] hydrolase-like protein 2; [Protein ADP-ribosylserine] hydrolase
Alternative UPACC:
Q9NX46; Q53G94; Q6IAB8; Q9BY47
Background:
ADP-ribosylhydrolase ARH3, known for its roles in DNA damage response and cell death prevention, hydrolyzes ADP-ribose linked to serine residues and degrades free poly(ADP-ribose). Its activity is crucial in mitigating the effects of DNA damage and stress on cellular functions.
Therapeutic significance:
Given its involvement in neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, targeting ADP-ribosylhydrolase ARH3 offers a promising avenue for therapeutic intervention in this debilitating disorder.
