NPJ drug discoveryPub Date : 2025-01-01Epub Date: 2025-03-04DOI: 10.1038/s44386-025-00006-5
Karla P Godinez-Macias, Daisy Chen, J Lincoln Wallis, Miles G Siegel, Anna Adam, Selina Bopp, Krypton Carolino, Lauren B Coulson, Greg Durst, Vandana Thathy, Lisl Esherick, Madeline A Farringer, Erika L Flannery, Barbara Forte, Tiqing Liu, Luma Godoy Magalhaes, Anil K Gupta, Eva S Istvan, Tiantian Jiang, Krittikorn Kumpornsin, Karen Lobb, Kyle J McLean, Igor M R Moura, John Okombo, N Connor Payne, Andrew Plater, Srinivasa P S Rao, Jair L Siqueira-Neto, Bente A Somsen, Robert L Summers, Rumin Zhang, Michael K Gilson, Francisco-Javier Gamo, Brice Campo, Beatriz Baragaña, James Duffy, Ian H Gilbert, Amanda K Lukens, Koen J Dechering, Jacquin C Niles, Case W McNamara, Xiu Cheng, Lyn-Marie Birkholtz, Alfred W Bronkhorst, David A Fidock, Dyann F Wirth, Daniel E Goldberg, Marcus C S Lee, Elizabeth A Winzeler
{"title":"Revisiting the <i>Plasmodium falciparum</i> druggable genome using predicted structures and data mining.","authors":"Karla P Godinez-Macias, Daisy Chen, J Lincoln Wallis, Miles G Siegel, Anna Adam, Selina Bopp, Krypton Carolino, Lauren B Coulson, Greg Durst, Vandana Thathy, Lisl Esherick, Madeline A Farringer, Erika L Flannery, Barbara Forte, Tiqing Liu, Luma Godoy Magalhaes, Anil K Gupta, Eva S Istvan, Tiantian Jiang, Krittikorn Kumpornsin, Karen Lobb, Kyle J McLean, Igor M R Moura, John Okombo, N Connor Payne, Andrew Plater, Srinivasa P S Rao, Jair L Siqueira-Neto, Bente A Somsen, Robert L Summers, Rumin Zhang, Michael K Gilson, Francisco-Javier Gamo, Brice Campo, Beatriz Baragaña, James Duffy, Ian H Gilbert, Amanda K Lukens, Koen J Dechering, Jacquin C Niles, Case W McNamara, Xiu Cheng, Lyn-Marie Birkholtz, Alfred W Bronkhorst, David A Fidock, Dyann F Wirth, Daniel E Goldberg, Marcus C S Lee, Elizabeth A Winzeler","doi":"10.1038/s44386-025-00006-5","DOIUrl":"10.1038/s44386-025-00006-5","url":null,"abstract":"<p><p>Identification of novel drug targets is a key component of modern drug discovery. While antimalarial targets are often identified through the mechanism of action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space is also constrained by existing compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction, we systematically assessed the <i>Plasmodium falciparum</i> genome and identified 867 candidate protein targets with evidence of small-molecule binding and blood-stage essentiality. Of these, 540 proteins showed strong essentiality evidence and lack inhibitors that have progressed to clinical trials. Expert review and rubric-based scoring of this subset based on additional criteria such as selectivity, structural information, and assay developability yielded 27 high-priority antimalarial target candidates. This study also provides a genome-wide data resource for <i>P. falciparum</i> and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets.</p>","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NPJ drug discoveryPub Date : 2025-01-01Epub Date: 2025-04-02DOI: 10.1038/s44386-025-00008-3
Amit K Verma, Robbert Q Kim, Dirk A Lamprecht, Clara Aguilar-Pérez, Sarah Wong, Nicolas Veziris, Alexandra Aubry, José M Bartolomé-Nebreda, Rodrigo J Carbajo, Jennefer Wetzel, Meindert H Lamers
{"title":"Structural and mechanistic study of a novel inhibitor analogue of <i>M. tuberculosis</i> cytochrome bc<sub>1</sub>:aa<sub>3</sub>.","authors":"Amit K Verma, Robbert Q Kim, Dirk A Lamprecht, Clara Aguilar-Pérez, Sarah Wong, Nicolas Veziris, Alexandra Aubry, José M Bartolomé-Nebreda, Rodrigo J Carbajo, Jennefer Wetzel, Meindert H Lamers","doi":"10.1038/s44386-025-00008-3","DOIUrl":"10.1038/s44386-025-00008-3","url":null,"abstract":"<p><p>Drug-resistant tuberculosis (TB) continues to challenge treatment options, necessitating the exploration of new compounds of novel targets. The mycobacterial respiratory complex cytochrome bc<sub>1</sub>:aa<sub>3</sub> has emerged as a promising target, exemplified by the success of first-in-class inhibitor Q203 in phase 2 clinical trials. However, to fully exploit the potential of this target and to identify the best-in-class inhibitor more compounds need evaluation. Here, we introduce JNJ-2901, a novel Q203 analogue, that demonstrates activity against multidrug-resistant <i>M. tuberculosis</i> clinical strains at sub-nanomolar concentration and 4-log reduction in bacterial burden in a mouse model of TB infection. Inhibitory studies on purified enzymes validate the nanomolar inhibitions observed in mycobacterial cells. Additionally, cryo-EM structure analysis of cytochrome bc<sub>1</sub>:aa<sub>3</sub> bound to JNJ-2901 reveals the binding pocket at the menaquinol oxidation site (Qp), akin to other substate analogue inhibitors like Q203 and TB47. Validation of the binding site is further achieved by generating and isolating the JNJ-2901 resistant mutations in <i>M. tuberculosis</i>, followed by purification and resistance analysis of the resistant cytochrome bc<sub>1</sub>:aa<sub>3</sub> complex. Our comprehensive work lays the foundation for further clinical validations of JNJ-2901.</p>","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":"6"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NPJ drug discoveryPub Date : 2025-01-01Epub Date: 2025-05-12DOI: 10.1038/s44386-025-00011-8
Brian E Krumm, Bryan L Roth
{"title":"Intracellular GPCR modulators enable precision pharmacology.","authors":"Brian E Krumm, Bryan L Roth","doi":"10.1038/s44386-025-00011-8","DOIUrl":"https://doi.org/10.1038/s44386-025-00011-8","url":null,"abstract":"<p><p>G-protein-coupled receptors (GPCRs) have proven to be the most successful target class for drug discovery but their complicated signal transduction pathways cause difficulties for drug development. Recently, ligands have been identified that engage an intracellular binding site which promotes pathway biased signal in cooperation with orthosteric ligands. Here, we explore the topic of biased signaling and intracellular modulators to understand their application for precision pharmacology of Class A or Rhodopsin-Like GPCRs.</p>","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":"8"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12069105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NPJ drug discoveryPub Date : 2025-01-01Epub Date: 2025-05-02DOI: 10.1038/s44386-025-00009-2
Whitaker Cohn, Jesus Campagna, Dongwook Wi, Jessica T Lee, Sahiba Beniwal, Gazmend Elezi, Chunni Zhu, Barbara Jagodzinska, Julian Whitelegge, Robert Damoiseaux, Varghese John
{"title":"Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer's disease mice.","authors":"Whitaker Cohn, Jesus Campagna, Dongwook Wi, Jessica T Lee, Sahiba Beniwal, Gazmend Elezi, Chunni Zhu, Barbara Jagodzinska, Julian Whitelegge, Robert Damoiseaux, Varghese John","doi":"10.1038/s44386-025-00009-2","DOIUrl":"https://doi.org/10.1038/s44386-025-00009-2","url":null,"abstract":"<p><p>Despite substantial research and drug discovery efforts, Alzheimer's Disease (AD) remains the sixth leading cause of death in the United States, underscoring the urgent need for novel therapeutic targets. A mutation in the clusterin (CLU) gene that hinders expression of the cyto-protective secreted isoform of clusterin (sCLU) that affects the aggregation and clearance of two key proteins implicated in AD, Aβ and tau, is the third most significant genetic risk factor for late-onset AD. Here, we present findings from our drug discovery program to identify small molecules that enhance sCLU levels and assess their impact on AD pathology and cognition in a murine model of AD. A high-throughput screening campaign identified two classes of epigenetic modulators that increase sCLU levels with subsequent medicinal chemistry efforts leading to bromodomain and extra-terminal (BET) inhibitor new chemical entities (NCEs) with enhanced potency, drug-like properties, and oral brain bioavailability. The lead candidate NCE, DDL-357, increased brain sCLU in the murine ApoE4TR-5XFAD model of AD in a subchronic study. In a follow-up chronic study in the murine 3xTg-AD model, DDL-357 reduced phospho-tau in brain and led to improvements in mouse performance and memory in the Barnes maze testing paradigm. Proteomic analysis of brain tissue from both AD models revealed changes in proteins involved in mitochondrial function and synaptic plasticity. These findings reveal the potential of sCLU enhancement as a target for therapeutic development in AD and support the continued development of the preclinical lead candidate.</p>","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":"7"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NPJ drug discoveryPub Date : 2025-01-01Epub Date: 2025-07-03DOI: 10.1038/s44386-025-00019-0
Mayako Michino, Jeremie Vendome, Irina Kufareva
{"title":"AI meets physics in computational structure-based drug discovery for GPCRs.","authors":"Mayako Michino, Jeremie Vendome, Irina Kufareva","doi":"10.1038/s44386-025-00019-0","DOIUrl":"10.1038/s44386-025-00019-0","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are a prominent class of therapeutic targets for which structure-based drug discovery (SBDD) has traditionally been challenging to apply. However, recent artificial intelligence (AI)-powered breakthroughs have opened new avenues. Here, we discuss the impact of computational models on hit discovery and lead optimization for GPCRs. We also provide best practices for generating and validating predictive models for prospective use.</p>","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":"16"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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