Virtual Screening of Histone Lysine Demethylase(JMJD2) identifies new inhibitors
Bibliographic record
Abstract
The JmjC domain-containing proteins are hydroxylases that confer posttranslational modifications on histone tails, by removing methylation marks on methylated lysine residues. This serves to either promote or repress gene transcription. The JMJD2A-D family members include the enzyme Jumonji domain 2C (JMJD2C), which specifically demethylates di- and trimethylated histone H3 at Lys 9 or Lys 36.[1] Dysregulation of JMJD2C has been implicated in prostate, colonic, and breast cancer as the demethylase can modify the expression levels of oncogenes.[2] The goal of the present study was to identify potent and selective small-molecule inhibitors of JMJD2C, to be used as chemical biology tools to further investigate the role of JMJD2C in cell proliferation and survival. Using high-resolution crystal structures of the JMJD2 subfamily members as templates, we have performed a small molecule virtual docking screen. From the ~3 million molecules that were docked, this experiment identified 21 compounds as possible leads. These compounds were tested against JMJD2C in enzymatic assays and here we report an overall hit rate of 76%, with 8 compounds demonstrating an IC50 of 176μM to 1.18μM. A molecule containing a salicylate core was selected as a candidate for optimization and thus far we have completed several rounds of iterative target-specific compound docking, hybrid molecule design, compound synthesis and in vitro characterization. Notably, our method demonstrated a substantial increase in potency when we linked two docked fragments together and further derivatized this new scaffold, through which we have successfully derived a 65nM inhibitor of JMJD2C. A compound representing the inhibitor scaffold has been co-crystallized with JMJD2A to a resolution of 2.4 Å. In the crystal structure each asymmetric unit contains two JMJD2A monomers, each bound to a single inhibitor molecule. This complex-structure superposes well with the docked pose for the hybrid series of compounds. We are now focusing our efforts on identifying an inhibitor that is selective for the JMJD2 family over other JmjC domain-containing proteins.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".