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 DNA mismatch repair protein Msh6 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 DNA mismatch repair protein Msh6 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 DNA mismatch repair protein Msh6, 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 DNA mismatch repair protein Msh6. 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 DNA mismatch repair protein Msh6. 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 DNA mismatch repair protein Msh6 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.
DNA mismatch repair protein Msh6
partner:
Reaxense
upacc:
P52701
UPID:
MSH6_HUMAN
Alternative names:
G/T mismatch-binding protein; MutS protein homolog 6; MutS-alpha 160 kDa subunit
Alternative UPACC:
P52701; B4DF41; B4E3I4; F5H2F9; O43706; O43917; Q8TCX4; Q9BTB5
Background:
DNA mismatch repair protein Msh6, also known as G/T mismatch-binding protein, plays a crucial role in the post-replicative DNA mismatch repair system (MMR). It forms a heterodimer with MSH2 to create MutS alpha, which identifies and initiates repair of DNA mismatches. This protein is essential for maintaining genomic stability by recognizing and repairing base mismatches and insertion-deletion loops, thereby preventing mutations that could lead to cancer.
Therapeutic significance:
Msh6 is directly linked to Lynch syndrome 5, endometrial cancer, mismatch repair cancer syndrome 3, and colorectal cancer. Its pivotal role in DNA repair pathways makes it a significant target for therapeutic strategies aimed at enhancing DNA repair mechanisms in cancer predisposition syndromes. Understanding the function of Msh6 could lead to breakthroughs in cancer treatment and prevention.
