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 General transcription and DNA repair factor IIH helicase subunit XPD 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 General transcription and DNA repair factor IIH helicase subunit XPD 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 General transcription and DNA repair factor IIH helicase subunit XPD, 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 General transcription and DNA repair factor IIH helicase subunit XPD. 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 General transcription and DNA repair factor IIH helicase subunit XPD. 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 General transcription and DNA repair factor IIH helicase subunit XPD 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.
General transcription and DNA repair factor IIH helicase subunit XPD
partner:
Reaxense
upacc:
P18074
UPID:
ERCC2_HUMAN
Alternative names:
Basic transcription factor 2 80 kDa subunit; CXPD; DNA excision repair protein ERCC-2; DNA repair protein complementing XP-D cells; TFIIH basal transcription factor complex 80 kDa subunit; Xeroderma pigmentosum group D-complementing protein
Alternative UPACC:
P18074; Q2TB78; Q2YDY2; Q7KZU6; Q8N721
Background:
The General transcription and DNA repair factor IIH helicase subunit XPD, known by alternative names such as DNA repair protein complementing XP-D cells and Xeroderma pigmentosum group D-complementing protein, plays a pivotal role in DNA repair and transcription. It is a key component of the TFIIH core complex, essential for nucleotide excision repair (NER) and transcription initiation by RNA polymerase II. Its ATP-dependent helicase activity is crucial for DNA opening during NER and transcription initiation, highlighting its multifaceted role in cellular DNA integrity and gene expression.
Therapeutic significance:
Given its critical functions in DNA repair and transcription, XPD is directly implicated in diseases such as Xeroderma pigmentosum complementation group D, Trichothiodystrophy 1, photosensitive, and Cerebro-oculo-facio-skeletal syndrome 2. These conditions underscore the protein's therapeutic significance, as understanding and targeting XPD's mechanisms could lead to innovative treatments for these genetic disorders, emphasizing the importance of research in this area.
