{"api_version":"1.1.0","engine_version":"gen-hit-design-2026.07-realchem","substrate_size":6,"targets":[{"target_symbol":"TYK2","target_full_name":"Tyrosine kinase 2","target_class":"small_molecule_tractable_kinase","structure_source":"PDB:6NZP","structure_source_notes":"TYK2 pseudokinase JH2 domain complexed with deucravacitinib - the seminal allosteric-inhibitor pocket","pathway_class":"autoimmune_JAK_STAT","diseases":["psoriasis","SLE","IBD","psoriatic_arthritis"],"india_frequency_signal":{"variant":"rs34536443","consequence":"P1104A (protective loss-of-function)","af_india_approx":0.021,"af_global":0.04,"signal_direction":"protective; India lower frequency = higher untreated autoimmune burden","verification_required":true},"existing_approved_drug":"deucravacitinib (Sotyktu, BMS 2022) + zasocitinib (Takeda Phase III)","white_space_note":"Approved drugs exist, but Indian-population dosing / response data thin. Confirms tractability of the pocket; India-specific inhibitor design remains open.","graph_evidence_strength":"HIGH","druggability_score":0.92},{"target_symbol":"STAT4","target_full_name":"Signal transducer and activator of transcription 4","target_class":"protein_binder_or_ppi_disruptor","structure_source":"PDB:5X0N","structure_source_notes":"STAT4 SH2 domain phosphopeptide-bound - PPI disruption opportunity","pathway_class":"autoimmune_Th1_Th17","diseases":["SLE","RA","T1D"],"india_frequency_signal":{"variant":"rs7574865","af_india_approx":0.27,"af_global":0.23,"signal_direction":"elevated in India · published in Indian SLE cohort literature","verification_required":true},"existing_approved_drug":null,"white_space_note":"No approved STAT4 inhibitor. Kinase-adjacent but SH2-domain-mediated PPI - genuine white space for both small-molecule PPI disruptors AND peptide binders.","graph_evidence_strength":"MODERATE","druggability_score":0.68},{"target_symbol":"IRF5","target_full_name":"Interferon regulatory factor 5","target_class":"protein_binder_or_ppi_disruptor","structure_source":"PDB:3DSH","structure_source_notes":"IRF5 IAD domain dimerization interface","pathway_class":"autoimmune_type_I_IFN","diseases":["SLE","RA","primary_biliary_cirrhosis"],"india_frequency_signal":{"variant":"rs2004640","af_india_approx":0.45,"af_global":0.35,"signal_direction":"elevated in India, published Indian SLE cohort association (Kaur et al.)","verification_required":true},"existing_approved_drug":null,"white_space_note":"No approved IRF5 modulator. Dimerization-interface PPI disruption is an active target class; binder track candidate.","graph_evidence_strength":"MODERATE","druggability_score":0.62},{"target_symbol":"HLA-B*15:02","target_full_name":"HLA-B*15:02 peptide-binding groove","target_class":"hla_peptide_groove_modulator","structure_source":"PDB:5W6A","structure_source_notes":"HLA-B*15:02 crystal structure — the SJS/TEN carbamazepine mechanism target","pathway_class":"autoimmune_antigen_presentation_and_drug_hypersensitivity","diseases":["SJS_TEN_carbamazepine_hypersensitivity","autoimmune_peptide_presentation"],"india_frequency_signal":{"variant":"HLA-B*15:02 allele","af_india_approx":0.09,"af_global":0.04,"signal_direction":"9% South Asian carrier frequency — highest-value India-specific HLA target","verification_required":true},"existing_approved_drug":null,"white_space_note":"No modulator of HLA-B*15:02 peptide presentation exists. Direct extension of IndoAutoImmune 2.0 structural work. Binder track flagship.","graph_evidence_strength":"HIGH","druggability_score":0.55},{"target_symbol":"PADI4","target_full_name":"Peptidyl arginine deiminase 4","target_class":"small_molecule_tractable_enzyme","structure_source":"PDB:2DEW","structure_source_notes":"Human PADI4 catalytic domain with substrate analog","pathway_class":"autoimmune_citrullination_RA","diseases":["RA","SLE"],"india_frequency_signal":{"variant":"rs2240336","af_india_approx":0.55,"af_global":0.47,"signal_direction":"elevated Indian RA cohort · published Kumar et al.","verification_required":true},"existing_approved_drug":null,"white_space_note":"No approved PADI4 inhibitor. Citrullination is the mechanistic driver of anti-CCP antibody generation in RA. Small-molecule track candidate.","graph_evidence_strength":"MODERATE","druggability_score":0.78},{"target_symbol":"IL23R","target_full_name":"Interleukin-23 receptor","target_class":"protein_binder_or_ppi_disruptor","structure_source":"AlphaFoldDB:IL23R","structure_source_notes":"AlphaFold-predicted IL23R extracellular domain","pathway_class":"autoimmune_Th17","diseases":["psoriasis","IBD","ankylosing_spondylitis"],"india_frequency_signal":{"variant":"rs11209026","af_india_approx":0.02,"af_global":0.06,"signal_direction":"protective allele lower in India - Indian population lacks the protection Northern Europeans enjoy","verification_required":true},"existing_approved_drug":"risankizumab / guselkumab (anti-IL23 antibodies)","white_space_note":"Approved antibodies exist. Small-molecule IL23R inhibitor remains open — oral bioavailability advantage over antibodies matters for Indian outpatient care.","graph_evidence_strength":"HIGH","druggability_score":0.72}],"small_molecule_candidate_pools":{"TYK2":3,"PADI4":1},"binder_candidate_pools":{"HLA-B*15:02":2,"STAT4":1,"IRF5":1},"gate_thresholds":{"boltz2_binding_confidence_min":0.6,"sa_score_max":6,"target_graph_evidence_min":["HIGH","MODERATE"]},"auditability_note":"This is the entire curated substrate the Phase 1 backend uses. Phase 2 swap-in: Neo4j Cypher on the full graph (targets) + DrugDiff sampling (small-mol candidates) + RFdiffusion3 + ProteinMPNN (binder candidates)."}