{ "case_study_id": "case_study_01_alzheimers_amyloid_pathway_candidate_discovery", "title": "Alzheimer\u0027s Amyloid-Pathway Candidate Discovery", "slug": "alzheimers-amyloid-discovery", "generated_on": "2026-04-07", "description": "FluxMateria root-cause Alzheimer\u0027s case study using a strict local discovery workflow to find BACE1-directed amyloid-pathway candidates while forcing CNS ADMET feasibility and explicit anti-target control against AChE and KCNH2.", "public_scope": "Public packet with top-shortlist SMILES disclosed. Internal engine references, internal search-space labels, near-miss structures, and provenance paths removed.", "discovery_brief": { "target_axis": "Amyloid-pathway discovery through BACE1 modulation", "controls": [ "Explicit anti-target control against symptomatic cholinergic drift", "Explicit cardiotoxicity control against KCNH2", "Strict CNS exposure and safety envelope" ], "constraints_summary": [ "BACE1 inhibition required", "BBB penetration required", "Permeability, hERG, PPB, and hepatotoxicity gates enforced", "Near-misses retained for interpretation only" ] }, "headline_metrics": { "broad_selective_passes": 48, "broad_enumerated": 707, "native_selective_passes": 34, "native_enumerated": 675, "verubecestat_sweep_passes": 7, "verubecestat_sweep_total": 100, "lanabecestat_sweep_passes": 4, "lanabecestat_sweep_total": 87, "top_hit_bace1_pki": 11.09, "independent_chemotypes_in_shortlist": 2 }, "workflow_summary": [ "Broad selective amyloid search", "Focused verubecestat-series refinement", "Focused lanabecestat-series refinement", "Native-only confirmation rerun" ], "final_shortlist": [ { "candidate_id": "FM-AD-01", "series": "lanabecestat-like", "motif": "dual-hydroxymethyl", "smiles": "CC(C)Oc1ccc(-c2nc3c(s2)n(-c2cc(F)c(CO)c(CO)c2)c(=O)n3C)cc1", "overall_score": 0.87113, "bace1_pki": 11.09, "ache_pki": 6.22, "herg_pIC50": 4.85, "permeability": -5.17, "ppb": 0.872, "why_it_ranked": "Best global balance of BACE1 strength, clean hERG margin, CNS-permissive permeability, and explicit anti-target compliance." }, { "candidate_id": "FM-AD-02", "series": "verubecestat-like", "motif": "single-hydroxymethyl", "smiles": "CC(NC(=O)c1ccc2c(c1)CN(C)C(=O)C2)c1nc2cccc(CO)c2s1", "overall_score": 0.870954, "bace1_pki": 11.08, "ache_pki": 6.26, "herg_pIC50": 4.92, "permeability": -5.33, "ppb": 0.753, "why_it_ranked": "Nearly tied for first and materially cleaner on PPB than the lanabecestat lead while preserving strong BACE1 potency." }, { "candidate_id": "FM-AD-03", "series": "lanabecestat-like", "motif": "hydroxy plus hydroxymethyl", "smiles": "CC(C)Oc1ccc(-c2nc3c(s2)n(-c2cc(F)c(O)c(CO)c2)c(=O)n3C)cc1", "overall_score": 0.87042, "bace1_pki": 11.05, "ache_pki": 6.19, "herg_pIC50": 4.8, "permeability": -5.67, "ppb": 0.901, "why_it_ranked": "Confirms the lanabecestat scaffold is robust across more than one passing substitution pattern." }, { "candidate_id": "FM-AD-04", "series": "lanabecestat-like", "motif": "dihydroxy fluoro core", "smiles": "CC(C)Oc1ccc(-c2nc3c(s2)n(-c2cc(O)c(O)c(F)c2)c(=O)n3C)cc1", "overall_score": 0.869696, "bace1_pki": 11.01, "ache_pki": 6.16, "herg_pIC50": 4.64, "permeability": -5.49, "ppb": 0.923, "why_it_ranked": "Most conservative hERG profile in the top tier while still staying inside the CNS gate." }, { "candidate_id": "FM-AD-05", "series": "verubecestat-like", "motif": "fluoro plus hydroxymethyl", "smiles": "CC(NC(=O)c1ccc2c(c1)CN(C)C(=O)C2)c1nc2ccc(F)c(CO)c2s1", "overall_score": 0.869696, "bace1_pki": 11.01, "ache_pki": 6.22, "herg_pIC50": 4.95, "permeability": -5.35, "ppb": 0.783, "why_it_ranked": "Shows the verubecestat series remains competitive after the lanabecestat expansion and gives a second strong scaffold family." } ], "near_misses": [ { "label": "Verubecestat regioisomer just outside permeability gate", "series": "verubecestat-like", "failed_on": "permeability", "actual": -6.09, "threshold": -6.0, "reason": "Strong BACE1 binding survived, but the molecule missed the CNS permeability cutoff by 0.09 log units." }, { "label": "Fluoro regioisomer with the same narrow permeability miss", "series": "verubecestat-like", "failed_on": "permeability", "actual": -6.13, "threshold": -6.0, "reason": "A small positional change preserved potency but moved the series just outside the hard CNS gate." }, { "label": "Dimethoxy analog rejected on hERG", "series": "bace1-other", "failed_on": "hERG", "actual": 5.17, "threshold": 5.0, "reason": "Binding remained attractive, but hERG moved above the hard cutoff and the compound was removed." }, { "label": "Lanabecestat amino plus hydroxymethyl analog rejected on hERG", "series": "lanabecestat-like", "failed_on": "hERG", "actual": 5.09, "threshold": 5.0, "reason": "This analog showed the right amyloid-directional binding pattern, but the hERG margin remained too narrow for the strict screen." } ], "key_findings": [ "The final shortlist is no longer a single chemotype story. Both lanabecestat-like and verubecestat-like BACE1-native series survive the strict screen.", "The top global hit came from the lanabecestat-like scaffold after a focused sweep exposed an underweighted dual-hydroxymethyl motif.", "The main bottleneck is now ADMET fine-tuning, especially narrow permeability and hERG misses, not loss of BACE1 affinity.", "Encoding AChE as an anti-target successfully forced the search away from symptomatic cholinergic rediscovery and toward amyloid-pathway chemistry." ], "limitations": [ "All values in this packet are computational predictions from FluxMateria, not wet-lab measurements.", "This case study supports an amyloid-pathway candidate discovery narrative through BACE1 modulation. It does not prove plaque clearance or clinical benefit.", "The website shortlist is based on the strict local discovery workflow and its top-ranked results, not on exhaustive medicinal chemistry expansion of every passing scaffold." ], "next_steps": [ "Biochemical BACE1 enzyme assay on the top 5 shortlisted candidates and top near-miss rescues.", "Counter-screen on AChE and hERG to confirm the computational selectivity and cardiotoxicity margins.", "Cell-based amyloid-beta production assay to test whether BACE1 binding translates into reduced amyloid-pathway output.", "Microsomal stability, solubility, and permeability confirmation on the lanabecestat and verubecestat lead subseries." ], "access_note": "Top-shortlist SMILES are disclosed publicly to support external research review. Near-miss structures, detailed workflow implementation details, and provenance are retained in internal records only." }