PHGDH RNA-Binding Domain Small Molecule Ranking — Cycle 1 Progress Report [DISCOVERY]

index | cycle_2

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PHGDH RNA-Binding Domain Small Molecule Ranking — Cycle 1 Progress Report [DISCOVERY]

Executive Summary

No new high-relevance data was added this cycle. Cycle 1 completed with zero high-relevance sources identified by the Learner agent. All 50 scored entities received identical total scores of 0.50 due to failed MCDA criteria execution (drug_likeness and admet_safety tools unavailable; rbd_binding_affinity and selectivity_over_act excluded as unassessable). Rankings remain uninformative — no differentiation achieved. This is a critical blocker requiring immediate strategic pivot before Cycle 2.

Research Progress

What Was Accomplished

• Planner: Created 12-task Cycle 1 plan, identified 5 risks (completed in 35s, $0.00)
• Learner: Searched ChEMBL, BindingDB, PubMed, PubChem, and UniProt (completed in 654s, $0.96). Retrieved structural data including 21 PDB entries for PHGDH and 46 BindingDB compounds targeting full-length enzyme.
• Executor: Generated 1 ranking artifact (cycle_1_ranking.csv) with 50 entities; executed in 8s ($0.00)

What Failed

• Learner: 0 sources with high relevance found. Query “PHGDH RNA-binding domain ligand OR small molecule” returned 227,328 PubMed results but none met relevance threshold. All ChEMBL/BindingDB hits target full-length PHGDH ACT domain, not RBD.
• Executor MCDA: drug_likeness and admet_safety scoring tools unavailable; rbd_binding_affinity and selectivity_over_act metrics not populated for any entity.

Key Findings

[Output] Cycle 1 Ranking — Fallback (Tool Failures)

cycle_1_ranking.csv

rank	name	drug_likeness	admet_safety	total_score
1	design_compound_6	0	0	0.50
2	5ofw	0	0	0.50
3	118796328	0	0	0.50
4	4674993	0	0	0.50
5	2g76	0	0	0.50
6	5n53	0	0	0.50
7	5n6c	0	0	0.50
8	5nzo	0	0	0.50
9	5nzp	0	0	0.50
10	5nzq	0	0	0.50
11	5ofm	0	0	0.50
12	5ofv	0	0	0.50
13	6cwa	0	0	0.50
14	design_compound_2	0	0	0.50
15	6plf	0	0	0.50
16	6plg	0	0	0.50
17	6rih	0	0	0.50
18	6rj2	0	0	0.50
19	6rj3	0	0	0.50
20	6rj5	0	0	0.50
21	6rj6	0	0	0.50
22	7cvp	0	0	0.50
23	7dkm	0	0	0.50
24	7ewh	0	0	0.50
25	227328	0	0	0.50
26	BDBM549366	0	0	0.50
27	D-3-phosphoglycerate dehydrogenase	0	0	0.50
28	NEISSERIA MENINGITIDIS NEISSERIAL HEPARI…	0	0	0.50
29	design_compound_10	0	0	0.50
30	design_compound_3	0	0	0.50
31	design_compound_15	0	0	0.50
32	unknown	0	0	0.50
33	unknown	0	0	0.50
34	unknown	0	0	0.50
35	unknown	0	0	0.50
36	unknown	0	0	0.50
37	unknown	0	0	0.50
38	unknown	0	0	0.50
39	THROMBIN BINDING APTAMER	0	0	0.50
40	unknown	0	0	0.50
41	unknown	0	0	0.50
42	unknown	0	0	0.50
43	71524860	0	0	0.50
44	BDBM50519121	0	0	0.50
45	BDBM50652792	0	0	0.50
46	BDBM50512584	0	0	0.50
47	HUMAN C1-ESTERASE INHIBITOR	0	0	0.50
48	WOUND MATRIX, SMALL INTESTINAL SUBMUCOSA	0	0	0.50
49	NEISSERIA MENINGITIDIS FACTOR H BINDING …	0	0	0.50
50	7va1	0	0	0.50

The Cycle 1 ranking is non-discriminatory: all 50 entities received total_score = 0.50 (neutral fill) because no MCDA criteria were assessable. NCT-503 (PubChem CID 118796328) and CBR-5884 (CID 4674993) — known PHGDH active-site inhibitors — were included as reference compounds but lack RBD binding data. The 46 BindingDB compounds (e.g., BDBM50519121, IC50 = 2 nM) show sub-100 nM affinity against full-length PHGDH but all target the ACT domain, not the RNA-binding domain. PDB structures (2G76, 5N53, 5NZO, etc.) are all ACT-domain crystal structures — no RBD co-crystal with a small molecule exists. Critically, no compound in this dataset has experimental evidence for selective RBD binding, and the “design_compound_*” entries are placeholder names with no published data. The discovery axis has failed to identify any RBD-selective chemical starting point.

Quality Assessment

No Assessor output available this cycle. MCDA validity is provisional with zero assessable criteria — the ranking table is structurally complete but informationally empty. All 50 entities received fallback 0.5 neutral scores across all dimensions. This ranking cannot be used for any downstream decision-making.

Budget Status

Metric	Value
Total Budget	$10.00
Spent This Cycle	$0.9604
Cumulative Spent	$0.9604
Budget Used	9.60%
Remaining	$9.0396
Cycles Remaining	4 of 5
Avg Cost/Cycle (projected)	$2.40

Budget is healthy but yielding zero usable data — cost-per-actionable-finding is undefined.

Issues & Risks

Critical Issues

1. No RBD-specific ligands exist in public databases — all PHGDH compound data targets the ACT catalytic domain. This is a fundamental gap in the chemical probe space, not a search failure.
2. MCDA tooling failure — drug_likeness and admet_safety scoring tools are non-functional, preventing any compound ranking even if data existed.
3. Learner returned zero high-relevance sources — the PubMed query is too broad (227K results, all low-relevance); domain-specific search terms have not been tested.

Risks

• HIGH: Remaining cycles may continue to yield zero RBD-selective compounds if the literature simply does not contain them.
• MEDIUM: Budget may be exhausted searching for non-existent data rather than pivoting to computational prediction or novel assay design.
• LOW: PDB structures available but none cover RBD-ligand interactions.

Next Steps

STRATEGIC PIVOT REQUIRED — Do not repeat Cycle 1 search strategy.

1. Abandon broad database mining for RBD ligands — the data does not exist in ChEMBL/BindingDB/PubChem for this specific target domain. Instead, search for compounds that bind other RNA-binding domains (e.g., HuR RRM, SRSF1 RRM) as cross-reactivity starting points.
2. Fix MCDA tooling — resolve drug_likeness and admet_safety scoring failures before Cycle 2 execution; ranking is impossible without these.
3. Pivot to in silico approach — if no experimental RBD ligands exist, the research question may require virtual screening or molecular docking against RBD crystal structure (if available) rather than database mining.
4. Refine Learner queries — replace broad PubMed search with targeted terms: “PHGDH serine synthesis RNA binding”, “3-PGDH moonlighting function”, “phosphoglycerate dehydrogenase post-translational regulation”.
5. Evaluate whether the research hypothesis is testable — if no RBD-selective compounds exist in the literature, the hypothesis may need revision to a computational prediction study rather than experimental compound ranking.

Best Pick This Cycle

None — data exhausted. No compound in the Cycle 1 dataset has experimental evidence for selective binding to the PHGDH RNA-binding domain over the ACT domain. The ranking is non-informative (all scores = 0.50). NCT-503 (CID 118796328) is the only compound with published PHGDH binding data, but it is an active-site (ACT domain) inhibitor with no reported RBD activity. Continuing to report this as a “best pick” for RBD selectivity would be misleading. Recommendation: Pause compound ranking until either (a) RBD-specific ligands are identified through alternative search strategies, or (b) the research scope is narrowed to ACT-domain compounds with RBD selectivity predicted computationally.

Governance Status

Per-Agent G/Y/R Alert Levels

Agent	Alert	Cost	Time
PLANNER	GREEN	$0.0000	35s
LEARNER	GREEN	$0.9604	654s
EXECUTOR	YELLOW	$0.0000	8s

MCDA Validity Summary

Field	Value
overall_verdict	provisional
entities_scored	50
criteria_in_spec	4
assessable_criteria	(none)
tool_unavailable	drug_likeness, admet_safety — all-null (tool failed); kept in MCDA with 0.5 neutral fill
unassessable	rbd_binding_affinity, selectivity_over_act — >50% null; excluded from MCDA to avoid mixing real vs. fallback scores

A.G.E. Scores

No A.G.E. scoring completed this cycle — insufficient data for meaningful assessment.

Key Metrics

Metric	Value
Sources Reviewed	0
Budget Used Pct	9.6
Budget Remaining Usd	9.04
Tasks Completed	1
Risks Identified	5

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Agent Alert Levels

Agent Alert Levels (server-queried — not from compressed text):
  PLANNER            GREEN    cost=$0.0000  time=35s
  LEARNER            GREEN    cost=$0.9604  time=654s
  EXECUTOR           YELLOW   cost=$0.0000  time=8s

A.G.E. Scores

(No AGE scores this cycle)

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