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 DENN domain-containing protein 5A 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 DENN domain-containing protein 5A 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 DENN domain-containing protein 5A, 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 DENN domain-containing protein 5A. 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 DENN domain-containing protein 5A. 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 DENN domain-containing protein 5A 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.
DENN domain-containing protein 5A
partner:
Reaxense
upacc:
Q6IQ26
UPID:
DEN5A_HUMAN
Alternative names:
Rab6-interacting protein 1
Alternative UPACC:
Q6IQ26; B4DJ15; E9PS91; Q96GN3; Q9H6U7; Q9UFV0; Q9UPR1
Background:
DENN domain-containing protein 5A, also known as Rab6-interacting protein 1, plays a crucial role as a guanine nucleotide exchange factor (GEF). It primarily activates RAB6A and RAB39A/B, facilitating the conversion of GDP-bound Rab proteins into their active GTP-bound form. This protein is instrumental in the negative regulation of neurite outgrowth, highlighting its significance in neuronal development and function.
Therapeutic significance:
The protein is linked to Developmental and epileptic encephalopathy 49 (DEE49), a severe autosomal recessive disorder characterized by neonatal seizures, global developmental delay, intellectual disability, cerebral calcifications, and coarse facial features. Understanding the role of DENN domain-containing protein 5A in DEE49 could pave the way for novel therapeutic strategies targeting this debilitating condition.
