{"doi":"10.1002/cmdc.202500024","title":"A Novel Inhibitor against the Bromodomain Protein 1 of the Malaria Pathogen\n                    <i>Plasmodium Falciparum</i>","abstract":"<jats:p>\n                    The rise of drug resistances in malaria necessitates the exploration of novel therapeutic strategies. Targeting epigenetic pathways could open new, promising treatment avenues. In this study, the focus is on the essential Bromodomain protein 1 (\n                    <jats:italic>Pf</jats:italic>\n                    BDP1) of the malaria pathogen\n                    <jats:italic>Plasmodium falciparum.</jats:italic>\n                    Utilizing the pan‐selective bromodomain inhibitor MPM6, a potent initial hit is identified and it is subsequently developed into a nanomolar binder. Through a combination of virtual docking, isothermal titration calorimetry, and X‐ray crystallography, the molecular interactions of the new inhibitors with the bromodomain (BRD) of the protein (\n                    <jats:italic>Pf</jats:italic>\n                    BDP1‐BRD) are elucidated. The findings include the first co‐crystallized inhibitors with the structures of\n                    <jats:italic>Pf</jats:italic>\n                    BRD1‐BRD as well as the bromodomain of the close homologous protein of\n                    <jats:italic>Plasmodium vivax</jats:italic>\n                    (\n                    <jats:italic>Pv</jats:italic>\n                    BDP1‐BRD). The structures provide new insights into their binding mechanisms. Further validation using conditional knockdown of\n                    <jats:italic>Pf</jats:italic>\n                    BDP1 in\n                    <jats:italic>P. falciparum</jats:italic>\n                    demonstrates parasite sensitivity to the inhibitor, underscoring its potential in a targeted therapeutic approach against malaria.\n                  </jats:p>","journal":"ChemMedChem","year":2025,"id":614749,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1584208,"name":"Robin Warstat","orcid":null,"position":1,"is_corresponding":false},{"id":1584209,"name":"Kay Kristin Rechten","orcid":null,"position":2,"is_corresponding":false},{"id":1584210,"name":"Philip Theuer","orcid":null,"position":3,"is_corresponding":false},{"id":1584211,"name":"Magdalena Schustereder","orcid":null,"position":4,"is_corresponding":false},{"id":1584212,"name":"Sophie Clavey","orcid":null,"position":5,"is_corresponding":false},{"id":1584213,"name":"Bernhard Breit","orcid":"0000-0002-2514-3898","position":6,"is_corresponding":false},{"id":229092,"name":"Oliver Einsle","orcid":"0000-0001-8722-2893","position":7,"is_corresponding":false},{"id":1584214,"name":"Martin Hügle","orcid":"0000-0002-2830-7130","position":8,"is_corresponding":false},{"id":891963,"name":"Michaela Petter","orcid":"0000-0002-1837-2756","position":9,"is_corresponding":false},{"id":3233,"name":"Stefan Günther","orcid":"0000-0002-5594-4549","position":10,"is_corresponding":false},{"id":1584207,"name":"Marius Amann","orcid":"0000-0001-7594-3810","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"A Novel Inhibitor against the Bromodomain Protein 1 of the Malaria Pathogen\n                    <i>Plasmodium Falciparum</i>","abstract":"<jats:p>\n                    The rise of drug resistances in malaria necessitates the exploration of novel therapeutic strategies. Targeting epigenetic pathways could open new, promising treatment avenues. In this study, the focus is on the essential Bromodomain protein 1 (\n                    <jats:italic>Pf</jats:italic>\n                    BDP1) of the malaria pathogen\n                    <jats:italic>Plasmodium falciparum.</jats:italic>\n                    Utilizing the pan‐selective bromodomain inhibitor MPM6, a potent initial hit is identified and it is subsequently developed into a nanomolar binder. Through a combination of virtual docking, isothermal titration calorimetry, and X‐ray crystallography, the molecular interactions of the new inhibitors with the bromodomain (BRD) of the protein (\n                    <jats:italic>Pf</jats:italic>\n                    BDP1‐BRD) are elucidated. The findings include the first co‐crystallized inhibitors with the structures of\n                    <jats:italic>Pf</jats:italic>\n                    BRD1‐BRD as well as the bromodomain of the close homologous protein of\n                    <jats:italic>Plasmodium vivax</jats:italic>\n                    (\n                    <jats:italic>Pv</jats:italic>\n                    BDP1‐BRD). The structures provide new insights into their binding mechanisms. Further validation using conditional knockdown of\n                    <jats:italic>Pf</jats:italic>\n                    BDP1 in\n                    <jats:italic>P. falciparum</jats:italic>\n                    demonstrates parasite sensitivity to the inhibitor, underscoring its potential in a targeted therapeutic approach against malaria.\n                  </jats:p>","is_dataset_classified":null,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40099623","pmcid":"PMC12132910","openalex_id":"https://openalex.org/W4408550286","authors":[],"funders":[{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"RTG2202","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"RTG2740; Project number 447268119","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"unidentified","title":"unidentified"}],"total_grants":3,"fwci":4.2918,"citation_percentile":0.93482286,"influential_citations":0,"citation_trend":[{"year":2025,"count":2},{"year":2026,"count":2}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cmdc.202500024","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cmdc.202500024","host_type":"publisher"},{"url":"https://chemistry-europe.onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.202500024","host_type":"publisher"},{"url":"https://doi.org/10.1002/cmdc.202500024","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40099623","host_type":"repository"},{"url":"https://www.dora.lib4ri.ch/psi/item/psi:73955","host_type":"repository"},{"url":"https://open.fau.de/handle/openfau/36883","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12132910","host_type":"repository"},{"url":"https://freidok.uni-freiburg.de/data/265359","host_type":"repository"},{"url":"https://www.dora.lib4ri.ch/psi/dload/psi:73955/PDF/view","host_type":"repository"},{"url":"https://open.fau.de/bitstreams/564424ec-5436-409b-a57f-8e6ba04b9cf2/download","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12132910","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12132910?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1002/cmdc.202500024","host_type":""}],"fields_of_study":["Malaria Research and Control","Multiple Myeloma Research and Treatments","Complement system in diseases","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Antimalarials","Dose-Response Relationship, Drug","Humans","Plasmodium falciparum","Structure-Activity Relationship","Molecular Structure","Protozoan Proteins","Crystallography, X-Ray","Parasitic Sensitivity Tests","Molecular Docking Simulation"],"keywords":["Bromodomain","Plasmodium falciparum","Isothermal titration calorimetry","Virtual screening","Malaria","Biology","Pathogen","Computational biology","Drug discovery","Chemistry","Epigenetics","Biochemistry","Microbiology","Immunology","Gene","Plasmodium","Inhibitors","Antiprotozoal agents","Molecular Structure","Dose-Response Relationship, Drug","Protozoan Proteins","Crystallography, X-Ray","Molecular Docking Simulation","Antimalarials","Structure-Activity Relationship","Parasitic Sensitivity Tests","Humans","Research Article"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T16:06:00.883821Z","pmid":null,"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":[]}