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 Cytochrome P450 1A2 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 Cytochrome P450 1A2 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 Cytochrome P450 1A2, 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 Cytochrome P450 1A2. 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 Cytochrome P450 1A2. 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 Cytochrome P450 1A2 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.
Cytochrome P450 1A2
partner:
Reaxense
upacc:
P05177
UPID:
CP1A2_HUMAN
Alternative names:
CYPIA2; Cholesterol 25-hydroxylase; Cytochrome P(3)450; Cytochrome P450 4; Cytochrome P450-P3; Hydroperoxy icosatetraenoate dehydratase
Alternative UPACC:
P05177; Q16754; Q6NWU3; Q6NWU5; Q9BXX7; Q9UK49
Background:
Cytochrome P450 1A2, known by alternative names such as CYPIA2 and Cholesterol 25-hydroxylase, plays a pivotal role in the metabolism of various substances. This enzyme is crucial for the metabolism of fatty acids, steroid hormones, and vitamins. It operates by inserting one oxygen atom into a substrate and reducing the second into a water molecule, a process supported by NADPH via cytochrome P450 reductase. Notably, it exhibits high catalytic activity for the formation of hydroxyestrogens and metabolizes cholesterol towards 25-hydroxycholesterol, crucial for cellular cholesterol homeostasis.
Therapeutic significance:
Understanding the role of Cytochrome P450 1A2 could open doors to potential therapeutic strategies. Its involvement in the metabolism of endogenous substrates and xenobiotics highlights its potential as a target for modulating various metabolic pathways, offering avenues for the development of novel therapeutic interventions.
