{"id":"AIBD-0658","title":"AlphaFold2 models of two receptors yield new ligands at hit rates matching experimental structures in large docking screens","summary":"UCSF-led teams docked up to 1.6 billion molecules against AlphaFold2 models of the sigma-2 and 5-HT2A receptors; hit rates (54% and 26%) matched those from experimental structures.","date_observed":"2024-06-21","date_basis":"source publication","date_precision":"day","benefit_status":"reported","source_collection":null,"source_entry":null,"account":"Researchers at the University of California, San Francisco, the University of North Carolina at Chapel Hill, Stanford University, Harvard Medical School and The Rockefeller University docked ultralarge chemical libraries against unrefined AlphaFold2 models of the sigma-2 receptor and the serotonin 2A (5-HT2A) receptor, and against experimental structures of the same receptors. They synthesized and tested hundreds of top-ranked molecules. For sigma-2, 64 of 119 molecules from the AlphaFold2 model were active, a hit rate of 54%, against 51% for the crystal structure. For 5-HT2A, 42 of 161 molecules from the AlphaFold2 model bound, a hit rate of 26%, against 23% for the cryo-EM structure, and the three strongest binders (15 to 24 nM) came from the AlphaFold2 campaign. The differences were not statistically significant. A cryo-EM structure of one new agonist with 5-HT2A agreed closely with the docked pose. Science published the study on 21 June 2024. The authors note that retrospective tests with known ligands had favored the experimental structures and that functional hit rates for 5-HT2A were low, in the range of 1 to 5%. The authors tested two receptors.","category":"benefit created","unexpected":true,"purpose":"AlphaFold2 was built to predict protein structures. Use of the predicted structures for ligand discovery is an application by independent researchers.","system":"AlphaFold2 (AF2) predicted structures used for large-library docking","model_version":null,"developer":"DeepMind","deployer":"University of California, San Francisco (Shoichet and Irwin laboratories) with the University of North Carolina at Chapel Hill (Roth laboratory), Stanford University and Harvard Medical School","location":"San Francisco and Stanford, California; Chapel Hill, North Carolina; Boston, Massachusetts; New York, New York, United States","domain":"Drug discovery","segment":null,"benefit_type":"Improved Knowledge Discovery","taxonomy_note":null,"registry_ids":{},"ratings":[{"group":"societal","depth":2,"reason":"The screens produced new sigma-2 and 5-HT2A ligands at hit rates equal to those from experimental structures (54% and 26%)."}],"ai_role":{"status":"assessed","statement":"The authors ran the same libraries and docking pipeline against the AlphaFold2 model and the experimental structure of each receptor, so they isolate the contribution of the predicted structure."},"evidence":[{"kind":"peer-reviewed study","citation":"Lyu J, Kapolka N, Gumpper R, et al. AlphaFold2 structures guide prospective ligand discovery. Science. 2024;384(6702):eadn6354.","title":"AlphaFold2 structures guide prospective ligand discovery","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11253030/","date":"2024-06-21","written_by":"deployer","quote":"Hit rates were high and similar for the experimental and AF2 structures, as were affinities."}],"replication":{"produced_by":["The AlphaFold2 models were predicted before the experimental structures were released.","Hundreds of top-ranked molecules were synthesized and tested for each structure."],"must_hold":["The binding pocket must be predicted with good accuracy.","Large make-on-demand libraries and binding assays must be available."],"echoes":[{"date":"2024-08-07","setting":"Uppsala University and Karolinska Institutet docking screen against AlphaFold models of TAAR1","model_version":null,"outcome":"recurred","source":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11305387/"}]},"paired_incident":null,"headline":"Predicted protein shapes guide a search for new drug leads","metric":"a hit rate of 54%, against 51% for the crystal structure","comparator":{"against":"Docking against the cryo-EM structure of the 5-HT2A receptor","before":"23% hit rate (51 of 223 molecules)","after":"26% hit rate (42 of 161 molecules)","basis":"measured","quote":"Meanwhile, 42 of the 161 molecules from docking against the AF2 model met this threshold, a hit rate of 26%","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11253030/"},"later":null,"value":null,"developer_country":"United Kingdom","deployer_country":"United States","unrated_because":null,"brief_notes":null,"brief":null,"revisions":[{"date":"2026-10-29","change":"Added the case.","source":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11253030/","editor":"AIBD"}],"confidence":"claimed","shade":"low","claim_status":"The deployer's account","claim_basis":"Sources: the deployer's peer-reviewed study. The cited evidence includes no independent source and no finding by a regulator or court.","case_jurisdictions":["United States"],"profile":{"case_id":"AIBD-0658","catalog_version":"1.0.0","source_fingerprint":"9f67e4c0d95186499316e5121de87f132e97868619d0f319a2cf02e6559df6da","collection_refs":[{"collection_id":"aibd","version":"2026-10-29"},{"collection_id":"viator","version":"2026-10-25"}],"source_ids":["AIBD-0658-source-0001"],"families":{"strategic assessments":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"Editorial assignment.","review_state":"not_assessed","coverage":"partial","record_ids":[]},"evaluations":{"state":"value_present","value":{"kind":"identifiers","identifiers":["AIBD-0658-evaluation-1"],"role":"Evaluations of the benefit"},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":[],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"partial","record_ids":["AIBD-0658-evaluation-1"]},"monetary observations":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"Editorial assignment.","review_state":"not_assessed","coverage":"partial","record_ids":[]},"institutional decisions":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"Editorial assignment.","review_state":"not_assessed","coverage":"partial","record_ids":[]}},"fields":{"actors[]":{"state":"value_present","value":{"kind":"record_fields","fields":{"developer":"DeepMind","deployer":"University of California, San Francisco (Shoichet and Irwin laboratories) with the University of North Carolina at Chapel Hill (Roth laboratory), Stanford University and Harvard Medical School"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["developer","deployer"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"actors[].ownership_control":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"ai_contribution":{"state":"value_present","value":{"kind":"record_fields","fields":{"ai_role":{"status":"assessed","statement":"The authors ran the same libraries and docking pipeline against the AlphaFold2 model and the experimental structure of each receptor, so they isolate the contribution of the predicted structure."}}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["ai_role"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"ai_relationship":{"state":"value_present","value":{"kind":"record_fields","fields":{"category":"benefit created","ai_role":{"status":"assessed","statement":"The authors ran the same libraries and docking pipeline against the AlphaFold2 model and the experimental structure of each receptor, so they isolate the contribution of the predicted structure."}}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["ai_role","category"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"assessments[].alternatives":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"assessments[].assessor_date":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"assessments[].depth":{"state":"value_present","value":{"kind":"record_fields","fields":{"ratings":[{"group":"societal","depth":2,"reason":"The screens produced new sigma-2 and 5-HT2A ligands at hit rates equal to those from experimental structures (54% and 26%)."}]}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["ratings"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"assessments[].display_confidence":{"state":"value_present","value":{"kind":"structured","data":{"confidence":"low","evidence_word":"claimed","claim_status":"The deployer's account","basis":"Sources: the deployer's peer-reviewed study. The cited evidence includes no independent source and no finding by a regulator or court.","interpretation":"Existing display rule preserved; the richer outcome-specific confidence question still needs review."}},"provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"assessments[].rationale":{"state":"value_present","value":{"kind":"record_fields","fields":{"ratings":[{"group":"societal","depth":2,"reason":"The screens produced new sigma-2 and 5-HT2A ligands at hit rates equal to those from experimental structures (54% and 26%)."}]}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["ratings"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"assessments[].rubric_version":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"assessments[].status_basis":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"assessments[].target":{"state":"value_present","value":{"kind":"record_fields","fields":{"ratings":[{"group":"societal","depth":2,"reason":"The screens produced new sigma-2 and 5-HT2A ligands at hit rates equal to those from experimental structures (54% and 26%)."}]}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["ratings"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"availability":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"brief":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"case_kind":{"state":"value_present","value":{"kind":"structured","data":{"classification":"evaluation or study","answer":"The case describes an evaluation or a study. A head-to-head prospective comparison of predicted and experimental structures.","scope":"The period and activity described in the case."}},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["account","evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"The case describes an evaluation or a study. A head-to-head prospective comparison of predicted and experimental structures.","inferred":false}},"case_links[]":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Compared with the incidents in the AI Incident Database snapshot of 26 October 2026.","record_fields":["paired_incident"],"source_refs":[]},"reason":"No incident in the AI Incident Database snapshot of 26 October 2026 concerns the same kind of system harming the same kind of stakeholder.","review_state":"reviewed","coverage":"partial"},"claims[].evidence_links":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"claims[].evidence_strength":{"state":"value_present","value":{"kind":"structured","data":{"answer":"The deployer's account. Sources: the deployer's peer-reviewed study. The cited evidence includes no independent source and no finding by a regulator or court.","evidence_word":"claimed","claim_status":"The deployer's account"}},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"The deployer's account. Sources: the deployer's peer-reviewed study. The cited evidence includes no independent source and no finding by a regulator or court.","inferred":false}},"claims[].missingness":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"claims[].proposition":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"cross_border_flows[]":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"decisions[].action_outcome":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"institutional decisions"},"decisions[].grounds":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"institutional decisions"},"decisions[].institution_task":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"institutional decisions"},"decisions[].success_criterion":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"institutional decisions"},"deployment_stage":{"state":"value_present","value":{"kind":"structured","data":{"classification":"laboratory test","answer":"The system was tested in a laboratory. Prospective docking and laboratory binding assays.","scope":"The period and activity described in the case."}},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["account","evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"The system was tested in a laboratory. Prospective docking and laboratory binding assays.","inferred":false}},"economics[].amount":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].costs[]":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].counterfactual":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].currency_price_basis":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].gross_net":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].measure_type":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].period_unit":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].realization":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].recipient_payer":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].return_payback":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"economics[].valuation_method":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"monetary observations"},"evaluations[].ai_uplift":{"state":"value_present","value":{"kind":"text","text":"Predicted structures matched experimental ones for ligand discovery."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Predicted structures matched experimental ones for ligand discovery.","inferred":false}},"evaluations[].comparator":{"state":"value_present","value":{"kind":"text","text":"Docking against experimental crystal and cryo-EM structures."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Docking against experimental crystal and cryo-EM structures.","inferred":false}},"evaluations[].design":{"state":"value_present","value":{"kind":"text","text":"Controlled observational."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Controlled observational.","inferred":false}},"evaluations[].effect":{"state":"value_present","value":{"kind":"text","text":"54% against 51% (sigma-2); 26% against 23% (5-HT2A); not significantly different."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"54% against 51% (sigma-2); 26% against 23% (5-HT2A); not significantly different.","inferred":false}},"evaluations[].exposure":{"state":"value_present","value":{"kind":"text","text":"Docking campaigns at UCSF; assays at UNC and elsewhere."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Docking campaigns at UCSF; assays at UNC and elsewhere.","inferred":false}},"evaluations[].id":{"state":"value_present","value":{"kind":"identifiers","identifiers":["AIBD-0658-evaluation-1"],"role":"Evaluations of the benefit"},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Controlled observational.","inferred":false}},"evaluations[].measurement_method":{"state":"value_present","value":{"kind":"text","text":"Radioligand binding assays of docked molecules; hit rate and affinity."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Radioligand binding assays of docked molecules; hit rate and affinity.","inferred":false}},"evaluations[].metric":{"state":"value_present","value":{"kind":"text","text":"Hit rate (actives per molecules tested) and affinity."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Hit rate (actives per molecules tested) and affinity.","inferred":false}},"evaluations[].reproduction_materials":{"state":"value_present","value":{"kind":"text","text":"Models, docking results and compounds described in the supplement; ZINC library public."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Models, docking results and compounds described in the supplement; ZINC library public.","inferred":false}},"evaluations[].setting_sample":{"state":"value_present","value":{"kind":"text","text":"About 500 synthesized molecules from docking 490 million (sigma-2) and 1.6 billion (5-HT2A) molecules."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"About 500 synthesized molecules from docking 490 million (sigma-2) and 1.6 billion (5-HT2A) molecules.","inferred":false}},"evaluations[].uncertainty_limitations":{"state":"value_present","value":{"kind":"text","text":"Two receptors; functional hit rates for 5-HT2A were 1 to 5%; retrospective enrichment favored experimental structures."},"provenance":{"kind":"source_review","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":["AIBD-0658-source-0001"],"reviewed_on":"2026-10-29"},"review_state":"reviewed","coverage":"complete","display":{"answer":"Two receptors; functional hit rates for 5-HT2A were 1 to 5%; retrospective enrichment favored experimental structures.","inferred":false}},"external_references[]":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"follow_up[]":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"human_oversight":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"id":{"state":"value_present","value":{"kind":"record_fields","fields":{"id":"AIBD-0658"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["id"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"infrastructure_dependencies[]":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"outcomes[].beneficiaries":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"outcomes[].beneficiary_count":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"outcomes[].benefit_type":{"state":"value_present","value":{"kind":"record_fields","fields":{"benefit_type":"Improved Knowledge Discovery"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["benefit_type"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"outcomes[].claim":{"state":"value_present","value":{"kind":"record_fields","fields":{"account":"Researchers at the University of California, San Francisco, the University of North Carolina at Chapel Hill, Stanford University, Harvard Medical School and The Rockefeller University docked ultralarge chemical libraries against unrefined AlphaFold2 models of the sigma-2 receptor and the serotonin 2A (5-HT2A) receptor, and against experimental structures of the same receptors. They synthesized and tested hundreds of top-ranked molecules. For sigma-2, 64 of 119 molecules from the AlphaFold2 model were active, a hit rate of 54%, against 51% for the crystal structure. For 5-HT2A, 42 of 161 molecules from the AlphaFold2 model bound, a hit rate of 26%, against 23% for the cryo-EM structure, and the three strongest binders (15 to 24 nM) came from the AlphaFold2 campaign. The differences were not statistically significant. A cryo-EM structure of one new agonist with 5-HT2A agreed closely with the docked pose. Science published the study on 21 June 2024. The authors note that retrospective tests with known ligands had favored the experimental structures and that functional hit rates for 5-HT2A were low, in the range of 1 to 5%. The authors tested two receptors.","benefit_type":"Improved Knowledge Discovery"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["account","benefit_type"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"outcomes[].distribution":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"outcomes[].duration":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"outcomes[].id":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"outcomes[].stakeholder_group":{"state":"value_present","value":{"kind":"record_fields","fields":{"ratings":[{"group":"societal","depth":2,"reason":"The screens produced new sigma-2 and 5-HT2A ligands at hit rates equal to those from experimental structures (54% and 26%)."}]}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["ratings"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"outcomes[].status":{"state":"value_present","value":{"kind":"record_fields","fields":{"benefit_status":"reported"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["benefit_status"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"outcomes[].tradeoffs":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"outcomes[].unexpected":{"state":"value_present","value":{"kind":"record_fields","fields":{"unexpected":true,"purpose":"AlphaFold2 was built to predict protein structures. Use of the predicted structures for ligand discovery is an application by independent researchers."}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["unexpected","purpose"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"places[]":{"state":"value_present","value":{"kind":"record_fields","fields":{"location":"San Francisco and Stanford, California; Chapel Hill, North Carolina; Boston, Massachusetts; New York, New York, United States","developer_country":"United Kingdom","deployer_country":"United States"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["location","developer_country","deployer_country"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"purpose":{"state":"value_present","value":{"kind":"record_fields","fields":{"purpose":"AlphaFold2 was built to predict protein structures. Use of the predicted structures for ligand discovery is an application by independent researchers."}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["purpose"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"record_dates":{"state":"value_present","value":{"kind":"record_fields","fields":{"date_observed":"2024-06-21","date_basis":"source publication","date_precision":"day","revisions":[{"date":"2026-10-29","change":"Added the case.","source":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11253030/","editor":"AIBD"}]}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["date_observed","date_basis","date_precision","revisions"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"replication.attempts[]":{"state":"value_present","value":{"kind":"record_fields","fields":{"replication":{"produced_by":["The AlphaFold2 models were predicted before the experimental structures were released.","Hundreds of top-ranked molecules were synthesized and tested for each structure."],"must_hold":["The binding pocket must be predicted with good accuracy.","Large make-on-demand libraries and binding assays must be available."],"echoes":[{"date":"2024-08-07","setting":"Uppsala University and Karolinska Institutet docking screen against AlphaFold models of TAAR1","outcome":"recurred","source":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11305387/"}]}}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["replication"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"replication.conditions":{"state":"value_present","value":{"kind":"record_fields","fields":{"replication":{"produced_by":["The AlphaFold2 models were predicted before the experimental structures were released.","Hundreds of top-ranked molecules were synthesized and tested for each structure."],"must_hold":["The binding pocket must be predicted with good accuracy.","Large make-on-demand libraries and binding assays must be available."],"echoes":[{"date":"2024-08-07","setting":"Uppsala University and Karolinska Institutet docking screen against AlphaFold models of TAAR1","outcome":"recurred","source":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11305387/"}]}}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["replication"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"revision_history[]":{"state":"value_present","value":{"kind":"record_fields","fields":{"revisions":[{"date":"2026-10-29","change":"Added the case.","source":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11253030/","editor":"AIBD"}]}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["revisions"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"sector":{"state":"value_present","value":{"kind":"record_fields","fields":{"domain":"Drug discovery"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["domain"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"sources[].access_version":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"sources[].citation_locator":{"state":"value_present","value":{"kind":"record_fields","fields":{"evidence":[{"kind":"peer-reviewed study","citation":"Lyu J, Kapolka N, Gumpper R, et al. AlphaFold2 structures guide prospective ligand discovery. Science. 2024;384(6702):eadn6354.","title":"AlphaFold2 structures guide prospective ligand discovery","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11253030/","date":"2024-06-21","written_by":"deployer","quote":"Hit rates were high and similar for the experimental and AF2 structures, as were affinities."}]}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"sources[].id":{"state":"value_present","value":{"kind":"identifiers","identifiers":["AIBD-0658-source-0001"],"role":"Existing evidence items, in their original order"},"provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"review_state":"record_mapped","coverage":"complete"},"sources[].language":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"sources[].relationship":{"state":"value_present","value":{"kind":"record_fields","fields":{"evidence":[{"kind":"peer-reviewed study","citation":"Lyu J, Kapolka N, Gumpper R, et al. AlphaFold2 structures guide prospective ligand discovery. Science. 2024;384(6702):eadn6354.","title":"AlphaFold2 structures guide prospective ligand discovery","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11253030/","date":"2024-06-21","written_by":"deployer","quote":"Hit rates were high and similar for the experimental and AF2 structures, as were affinities."}]}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["evidence"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"sources[].upstream_sources":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"strategic_assessments[]":{"state":"unresolved","review_state":"not_assessed","coverage":"partial","family":"strategic assessments"},"summary":{"state":"value_present","value":{"kind":"record_fields","fields":{"summary":"UCSF-led teams docked up to 1.6 billion molecules against AlphaFold2 models of the sigma-2 and 5-HT2A receptors; hit rates (54% and 26%) matched those from experimental structures.","account":"Researchers at the University of California, San Francisco, the University of North Carolina at Chapel Hill, Stanford University, Harvard Medical School and The Rockefeller University docked ultralarge chemical libraries against unrefined AlphaFold2 models of the sigma-2 receptor and the serotonin 2A (5-HT2A) receptor, and against experimental structures of the same receptors. They synthesized and tested hundreds of top-ranked molecules. For sigma-2, 64 of 119 molecules from the AlphaFold2 model were active, a hit rate of 54%, against 51% for the crystal structure. For 5-HT2A, 42 of 161 molecules from the AlphaFold2 model bound, a hit rate of 26%, against 23% for the cryo-EM structure, and the three strongest binders (15 to 24 nM) came from the AlphaFold2 campaign. The differences were not statistically significant. A cryo-EM structure of one new agonist with 5-HT2A agreed closely with the docked pose. Science published the study on 21 June 2024. The authors note that retrospective tests with known ligands had favored the experimental structures and that functional hit rates for 5-HT2A were low, in the range of 1 to 5%. The authors tested two receptors."}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["summary","account"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"systems[].autonomy_permissions":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"systems[].component_role":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"systems[].deployment_configuration":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"systems[].inputs_outputs":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"systems[].model_name":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"systems[].model_version":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"systems[].product_name":{"state":"value_present","value":{"kind":"record_fields","fields":{"system":"AlphaFold2 (AF2) predicted structures used for large-library docking"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["system"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"systems[].provider":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"taxonomy_crosswalks[]":{"state":"unresolved","provenance":{"kind":"curatorial","basis":"Editorial assignment.","record_fields":[],"source_refs":[]},"reason":"This is an explicit unresolved assignment: the sources on record do not settle this question.","review_state":"not_assessed","coverage":"partial"},"title":{"state":"value_present","value":{"kind":"record_fields","fields":{"title":"AlphaFold2 models of two receptors yield new ligands at hit rates matching experimental structures in large docking screens","headline":"Predicted protein shapes guide a search for new drug leads"}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["title","headline"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"},"version":{"state":"value_present","value":{"kind":"identifiers","identifiers":["868371375049b0287636ba955909b1a5dda9f10e03ae7c9d65c0ab258968e5a5"],"role":"SHA-256 of the complete public case and its assessments"},"provenance":{"kind":"curatorial","basis":"SHA-256 of the public case, its assessments, and its displayed answers and notes, excluding its own identifier and the derived coverage summary.","record_fields":[],"source_refs":[]},"review_state":"record_mapped","coverage":"complete"},"workflow":{"state":"value_present","value":{"kind":"record_fields","fields":{"account":"Researchers at the University of California, San Francisco, the University of North Carolina at Chapel Hill, Stanford University, Harvard Medical School and The Rockefeller University docked ultralarge chemical libraries against unrefined AlphaFold2 models of the sigma-2 receptor and the serotonin 2A (5-HT2A) receptor, and against experimental structures of the same receptors. They synthesized and tested hundreds of top-ranked molecules. For sigma-2, 64 of 119 molecules from the AlphaFold2 model were active, a hit rate of 54%, against 51% for the crystal structure. For 5-HT2A, 42 of 161 molecules from the AlphaFold2 model bound, a hit rate of 26%, against 23% for the cryo-EM structure, and the three strongest binders (15 to 24 nM) came from the AlphaFold2 campaign. The differences were not statistically significant. A cryo-EM structure of one new agonist with 5-HT2A agreed closely with the docked pose. Science published the study on 21 June 2024. The authors note that retrospective tests with known ligands had favored the experimental structures and that functional hit rates for 5-HT2A were low, in the range of 1 to 5%. The authors tested two receptors.","replication":{"produced_by":["The AlphaFold2 models were predicted before the experimental structures were released.","Hundreds of top-ranked molecules were synthesized and tested for each structure."],"must_hold":["The binding pocket must be predicted with good accuracy.","Large make-on-demand libraries and binding assays must be available."],"echoes":[{"date":"2024-08-07","setting":"Uppsala University and Karolinska Institutet docking screen against AlphaFold models of TAAR1","outcome":"recurred","source":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11305387/"}]}}},"provenance":{"kind":"legacy_record","basis":"Editorial assignment.","record_fields":["account","replication"],"source_refs":[]},"review_state":"record_mapped","coverage":"partial"}},"summary":{"total":91,"addressed":91,"known":42,"reviewed":15,"reviewed_complete":14,"reviewed_partial":1,"record_mapped":28,"review_not_assessed":48,"not_assessed":0,"complete":false,"by_state":{"value_present":42,"not_reported":0,"unresolved":49,"not_assessed":0,"not_applicable":0,"withheld":0,"source_unavailable":0}}},"presentation_version":"503bef916cf40cad399780860ce40af7b67321c8e2bd83c4b8fb73564f9df468"}