title: “PHGDH Project Brief” updated: 2026-04-18 source_of_truth: /Users/jakeclaw/.openclaw/workspace/project_info.md (Master-Blueprint)
PHGDH Project — what we know (distilled)
The target
PHGDH = D-3-phosphoglycerate dehydrogenase
- UniProt: O43175 (human)
- ChEMBL target: CHEMBL2311243 (from scavenger)
- Function: rate-limiting enzyme in the serine biosynthesis pathway (3-PG → 3-phosphohydroxypyruvate)
- Cofactor: NAD+ / NADH
- Quaternary structure: tetramer
- Key domains: substrate-binding (SBD), nucleotide-binding (NBD), allosteric-serine (ACT) regulatory domain, regulatory-binding domain (RBD)
Why this target (project thesis)
- Neurodegeneration angle (primary). PHGDH is dysregulated in
Alzheimer’s — evidence from proteomic and transcriptomic studies already
indexed in our wiki (
phgdh-dysregulation-in-alzheimers-disease-pathogenesis,phgdh-and-amyloid-beta-interactions). - Allosteric / RBD sites, not the active site. Active-site orthosteric inhibitors (NCT-503, CBR-5884) exist but have selectivity problems. Our thesis is that allosteric and RBD modulators can offer finer regulatory control — up OR down — for CNS application.
- Serine → D-serine → NMDA modulation. Serine biosynthesis is linked to D-serine (NMDA co-agonist). Tuning PHGDH tunes synaptic signaling, relevant for Alzheimer’s and other neurodegenerative diseases.
Structures we care about
| PDB | Form | Notes |
|---|---|---|
| 4NJN | apo human PHGDH tetramer | reference apo |
| 6RIH | with orthosteric ligand | active-site benchmark |
| 7S3R | with allosteric pocket bound | allosteric reference (if matches our thesis) |
Others to download as G-005 progresses.
Tools already in place
- Data scavenger — daily ChEMBL pull to
~/workers/data/phgdh/YYYY-MM-DD.jsonl(2613 rows of bioactivity in today’s file — SMILES, pChEMBL, standard_type, assay IDs) - Wiki (Hermes-built) — 17 PHGDH pages already in
~/wiki/general/and~/.openclaw/workspace/topics/covering: structure, SBDD, virtual screening, drug-discovery literature, deep-learning for binding affinity, serine pathway linkages, AD therapeutic strategies - Cheaha-HPC skill — templates for CPU, single-GPU, multi-GPU, and array sbatch; wrappers for submit / status / cancel
- UAB VPN — openconnect + credentials in place; W0 can VPN on demand to reach internal UAB resources
Near-term milestones (from BACKLOG.md)
- G-002: pChEMBL distribution figure (local — matplotlib)
- G-003: top-20 inhibitors table (local — pandas)
- G-004: PubMed sweep for allosteric/RBD literature (Hermes wiki-builder)
- G-005: PDB structure download + binding-site annotation (local — BioPython)
- G-006/G-007: Cheaha workspace setup + virtual-screening sbatch
- G-008: wiki page
phgdh-scavengersummarizing the pipeline - G-009: paper intro draft (Chrome-Claude)
- G-010: repo README + pipeline diagram
- G-011: January 2025 AI-drug-discovery digest
Success criteria (project level)
(Copied from PROJECT_PLAN.md for easy reference.)
- ≥ 30 days of PHGDH bioactivity data accumulated
- ≥ 100 source-validated PHGDH wiki pages
- ≥ 1 SBDD virtual-screening run completed on Cheaha
- Paper draft: intro + methods + preliminary results sections
- Slide deck: 20+ slides
- ≥ 30 consecutive autonomous days (only Duo pushes from Jake)
- 0 unresolved incidents in RESOLUTION_LOG for 7+ days
Note on project name drift
The project_info.md master-blueprint frontmatter says
“PHGDH-Allosteric-RBD-Binder” but the body says “PHAGE”. That was
a Gemma 4 tokenizer glitch when the model drafted the body. PHGDH is
correct; PHAGE is noise. This brief is canonical.
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