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 Caspase-9 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 Caspase-9 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 Caspase-9, 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 Caspase-9. 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 Caspase-9. 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 Caspase-9 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.
Caspase-9
partner:
Reaxense
upacc:
P55211
UPID:
CASP9_HUMAN
Alternative names:
Apoptotic protease Mch-6; Apoptotic protease-activating factor 3; ICE-like apoptotic protease 6
Alternative UPACC:
P55211; B4E1A3; O95348; Q53Y70; Q5JRU9; Q5UGI1; Q92852; Q9BQ62; Q9UEQ3; Q9UIJ8
Background:
Caspase-9, encoded by the gene with the accession number P55211, plays a pivotal role in the apoptotic pathway. It is activated in a cascade that involves the cleavage of caspase-3 (CASP3) or caspase-7 (CASP7), essential for apoptosis execution. This process is crucial for maintaining cellular homeostasis and responding to DNA damage. Caspase-9's activation is facilitated by its binding to Apaf-1 and is significantly influenced by ABL1/c-Abl in promoting apoptosis following DNA damage. Additionally, it can cleave poly(ADP-ribose) polymerase (PARP), further underscoring its role in apoptosis.
Therapeutic significance:
Understanding the role of Caspase-9 could open doors to potential therapeutic strategies. Its central role in apoptosis makes it a target for developing treatments that require the modulation of cell death, such as in cancer therapy, where the induction of apoptosis in tumor cells could be beneficial.
