{"doi":"10.1101/2023.11.15.567213","title":"Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction","abstract":"Summary Inherited cardiomyopathies are amongst the most common cardiac diseases worldwide, leading in the late-stage to heart failure and death. The most promising treatments against these diseases are small-molecules directly modulating the force produced by β-cardiac myosin, the molecular motor driving heart contraction. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activator Omecamtiv mecarbil and the inhibitor Mavacamten . In this work, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing β-cardiac myosin in the apo form or bound to Omecamtiv mecarbil or Mavacamten . Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":390625,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":582661,"name":"Julien Robert‐Paganin","orcid":"0000-0001-6102-2025","position":1,"is_corresponding":false},{"id":1162426,"name":"S. Réty","orcid":"0000-0002-2089-6727","position":2,"is_corresponding":false},{"id":353407,"name":"Carlos Kikuti","orcid":"0000-0001-5928-2776","position":3,"is_corresponding":false},{"id":1122516,"name":"Amandine David","orcid":"0000-0002-3284-4115","position":4,"is_corresponding":false},{"id":1162919,"name":"Gabriele Theumer","orcid":null,"position":5,"is_corresponding":false},{"id":1162920,"name":"Arndt W. Schmidt","orcid":null,"position":6,"is_corresponding":false},{"id":582270,"name":"Hans‐Joachim Knölker","orcid":"0000-0002-9631-5239","position":7,"is_corresponding":false},{"id":353410,"name":"Anne Houdusse","orcid":"0000-0002-8566-0336","position":8,"is_corresponding":false},{"id":582657,"name":"Daniel Auguin","orcid":"0000-0003-4713-9096","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T01:18:37.743462Z","pmid":"38014327","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}