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 NPC intracellular cholesterol transporter 1 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 NPC intracellular cholesterol transporter 1 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 NPC intracellular cholesterol transporter 1, 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 NPC intracellular cholesterol transporter 1. 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 NPC intracellular cholesterol transporter 1. 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 NPC intracellular cholesterol transporter 1 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.
NPC intracellular cholesterol transporter 1
partner:
Reaxense
upacc:
O15118
UPID:
NPC1_HUMAN
Alternative names:
Niemann-Pick C1 protein
Alternative UPACC:
O15118; B4DET3; Q9P130
Background:
NPC intracellular cholesterol transporter 1, also known as Niemann-Pick C1 protein, plays a pivotal role in cholesterol homeostasis. It facilitates the egress of cholesterol from the endosomal/lysosomal compartment, crucial for cellular lipid balance. The protein interacts with NPC2 for cholesterol transfer and binds oxysterol with higher affinity, indicating a nuanced role in lipid signaling and metabolism.
Therapeutic significance:
Niemann-Pick disease C1, a lysosomal storage disorder, is directly linked to mutations in the gene encoding this protein. Understanding its function and the molecular mechanisms underlying its interaction with cholesterol and other molecules could pave the way for targeted therapies, potentially alleviating the severe neurological and visceral symptoms associated with this condition.
