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 Homeobox protein Nkx-2.5 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 Homeobox protein Nkx-2.5 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 Homeobox protein Nkx-2.5, 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 Homeobox protein Nkx-2.5. 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 Homeobox protein Nkx-2.5. 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 Homeobox protein Nkx-2.5 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.
Homeobox protein Nkx-2.5
partner:
Reaxense
upacc:
P52952
UPID:
NKX25_HUMAN
Alternative names:
Cardiac-specific homeobox; Homeobox protein CSX; Homeobox protein NK-2 homolog E
Alternative UPACC:
P52952; A8K3K0; B4DNB6; E9PBU6
Background:
Homeobox protein Nkx-2.5, also known as cardiac-specific homeobox, plays a pivotal role in heart and spleen development. It acts as a transcriptional activator of NPPA/ANF in cooperation with GATA4 and may modulate expression of NPPA/ANF in the atrioventricular canal. This protein binds to the core DNA motif of NPPA promoter and is essential for spleen development alongside PBX1, through mechanisms involving CDKN2B repression.
Therapeutic significance:
Given its crucial role in the development of the heart, Homeobox protein Nkx-2.5 is linked to several congenital heart defects, including Atrial septal defect 7, Tetralogy of Fallot, and Hypoplastic left heart syndrome 2. Understanding the role of Homeobox protein Nkx-2.5 could open doors to potential therapeutic strategies for these conditions.
