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 Homogentisate 1,2-dioxygenase 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 Homogentisate 1,2-dioxygenase 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 Homogentisate 1,2-dioxygenase, 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 Homogentisate 1,2-dioxygenase. 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 Homogentisate 1,2-dioxygenase. 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 Homogentisate 1,2-dioxygenase 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.
Homogentisate 1,2-dioxygenase
partner:
Reaxense
upacc:
Q93099
UPID:
HGD_HUMAN
Alternative names:
Homogentisate oxygenase; Homogentisic acid oxidase; Homogentisicase
Alternative UPACC:
Q93099; A8K417; B2R8Z0
Background:
Homogentisate 1,2-dioxygenase, also known as Homogentisate oxygenase, plays a crucial role in the breakdown of amino acids phenylalanine and tyrosine. It catalyzes the conversion of homogentisate to maleylacetoacetate, a key step in the catabolic pathway. This enzyme's malfunction is directly linked to Alkaptonuria, a metabolic disorder characterized by urine that darkens upon standing and severe arthritis.
Therapeutic significance:
The direct association of Homogentisate 1,2-dioxygenase with Alkaptonuria highlights its therapeutic significance. Targeting this enzyme could lead to innovative treatments for Alkaptonuria, focusing on enzyme replacement or enhancement to correct the metabolic pathway.
