NPJ drug discovery最新文献_第6页

A Metabolism-Informed Neural Network Identifies Pathways Influencing the Potency and Toxicity of Antimicrobial Combinations. 代谢信息神经网络识别影响抗菌药物组合效力和毒性的途径。

NPJ drug discovery Pub Date : 2026-01-01 Epub Date: 2026-04-01 DOI: 10.1038/s44386-026-00042-9

Harkirat Singh Arora, Katherine Lev, Aaron Robida, Ramraj Velmurugan, Sriram Chandrasekaran

{"title":"A Metabolism-Informed Neural Network Identifies Pathways Influencing the Potency and Toxicity of Antimicrobial Combinations.","authors":"Harkirat Singh Arora, Katherine Lev, Aaron Robida, Ramraj Velmurugan, Sriram Chandrasekaran","doi":"10.1038/s44386-026-00042-9","DOIUrl":"10.1038/s44386-026-00042-9","url":null,"abstract":"Antimicrobial resistance poses a major global threat, driven by diminishing efficacy of current treatments and limited new therapies. Combination therapy with existing drugs offers a promising solution, yet current empirical screening methods are expensive and often lead to suboptimal efficacy and inadvertent toxicity. We introduce CALMA, a computational framework that quantitatively analyzes the potency-toxicity landscape of multi-drug combinations. Integrating genome-scale metabolic modeling with a neural network that reflects metabolic subsystems, CALMA enhances interpretability and prioritizes pathways influencing drug interactions. The incorporation of metabolic architecture in the neural network leads to over 92% reduction in model parameters, enabling it to learn generalizable mechanistic signals and reducing the experimental search space of optimal combinations by 97%. CALMA identified promising antimicrobial combinations against Escherichia coli and Mycobacterium tuberculosis that were antagonistic for kidney and liver toxicity and uncovered the nucleotide salvage pathway as a selective influencer of toxicity, which was validated in vitro. Mining of health records of over 400,000 patients showed reduced frequency of kidney side-effects in patients taking a vancomycin combination identified by CALMA. CALMA provides a rational, mechanistic approach to streamline combination treatment design.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"3 1","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13043290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147625467","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}

引用次数: 0

Large animal models for the assessment of snakebite envenoming therapies. 用于评估蛇咬伤治疗的大型动物模型。

NPJ drug discovery Pub Date : 2026-01-01 Epub Date: 2026-04-01 DOI: 10.1038/s44386-026-00043-8

Melisa Benard-Valle, Shirin Ahmadi, Cassandra M Modahl, Edgar Neri-Castro, Alejandro Alagón, Leslie Boyer, Anne Ljungars, Andreas H Laustsen

引用次数: 0

Accelerating GPCR drug discovery through computation and experiment integrated with direct detection of ligand binding events. 通过计算和实验结合直接检测配体结合事件，加速GPCR药物发现。

NPJ drug discovery Pub Date : 2026-01-01 Epub Date: 2026-04-09 DOI: 10.1038/s44386-026-00046-5

Judith Su, Stephen B Liggett, Soo-Kyung Kim, Donghwa Kim, William A Goddard

引用次数: 0

A review of deep learning approaches for drug synergy prediction in cancer. 癌症药物协同作用预测的深度学习方法综述。

NPJ drug discovery Pub Date : 2025-12-16 DOI: 10.1038/s44386-025-00034-1

Lei Li, Hongyu Zhang, Chunhou Zheng, Yansen Su

引用次数: 0

Preclinical characterization of EGT710, an oral non-peptidomimetic reversible covalent SARS-CoV-2 main protease inhibitor. 口服非肽类可逆性共价SARS-CoV-2主要蛋白酶抑制剂EGT710的临床前特征

NPJ drug discovery Pub Date : 2025-11-28 DOI: 10.1038/s44386-025-00030-5

Stephanie A Moquin, Suresh B Lakshminarayana, Kamal Kumar Balavenkatraman, Hilmar Schiller, Allison Claas, Barun Bhhatarai, Ioannis Loisios-Konstantinidis, Katarina Vulic, Chaitanya Kurhade, Birte K Kalveram, John Yun-Chung Chen, Jing Zou, Xuping Xie, Laura Tandeske, Dustin Dovala, Elizabeth Ornelas, Mark S Knapp, Daniel Fuller, Zachary Nguyen, David T Barkan, Lidiya Bebrevska, S Kirk Wright, Scott A Busby, Johanne Blais, Pei-Yong Shi, Suzanne Gaudet, Renee Bergeron, Hannah Yu, Julia Zack, Christopher Sarko, Feng Gu, James E Bradner, John A Tallarico, Thierry T Diagana, Julien P N Papillon

{"title":"Preclinical characterization of EGT710, an oral non-peptidomimetic reversible covalent SARS-CoV-2 main protease inhibitor.","authors":"Stephanie A Moquin, Suresh B Lakshminarayana, Kamal Kumar Balavenkatraman, Hilmar Schiller, Allison Claas, Barun Bhhatarai, Ioannis Loisios-Konstantinidis, Katarina Vulic, Chaitanya Kurhade, Birte K Kalveram, John Yun-Chung Chen, Jing Zou, Xuping Xie, Laura Tandeske, Dustin Dovala, Elizabeth Ornelas, Mark S Knapp, Daniel Fuller, Zachary Nguyen, David T Barkan, Lidiya Bebrevska, S Kirk Wright, Scott A Busby, Johanne Blais, Pei-Yong Shi, Suzanne Gaudet, Renee Bergeron, Hannah Yu, Julia Zack, Christopher Sarko, Feng Gu, James E Bradner, John A Tallarico, Thierry T Diagana, Julien P N Papillon","doi":"10.1038/s44386-025-00030-5","DOIUrl":"10.1038/s44386-025-00030-5","url":null,"abstract":"EGT710 is an orally bioavailable non-peptidomimetic reversible covalent coronavirus main protease (Mpro) inhibitor with low nM cellular activity against SARS-CoV-2. Twice daily dosing of 10 mg/kg of EGT710 decreased lung viral load in a mouse model of SARS-CoV-2 infection to below the limit of detection. Resistance selection resulted in the emergence of several Mpro mutations, with recombinant viruses containing L50F + E166A substitutions showing the largest shift in potency. Development of a viral kinetics model using viremia data from clinical trials, along with a human physiologically based pharmacokinetic model, predicted efficacy in humans with once daily oral doses of >360 mg. EGT710 displays favorable pharmacokinetic properties and an acceptable in vitro and in vivo safety profile, with human exposures at the recommended clinical dose of 600 mg predicted to be below the no adverse effect level in preclinical toxicology studies. Together, EGT710 has a promising preclinical profile and has completed a Phase I study.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364644","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}

引用次数: 0

A novel drug series optimized to address cystic fibrosis and other CFTR deficiency diseases of human airways. 一种新型药物系列优化治疗囊性纤维化和其他CFTR缺乏性疾病的人类气道。

NPJ drug discovery Pub Date : 2025-11-03 DOI: 10.1038/s44386-025-00026-1

Andras Rab, Jeong S Hong, Candela Manfredi, Disha Joshi, Sadhana Ponnaluri, William F Tracy, Yujie Luo, Xun Yang, Alexander A Kolykhalov, Huw M L Davies, Eric J Sorscher

{"title":"A novel drug series optimized to address cystic fibrosis and other CFTR deficiency diseases of human airways.","authors":"Andras Rab, Jeong S Hong, Candela Manfredi, Disha Joshi, Sadhana Ponnaluri, William F Tracy, Yujie Luo, Xun Yang, Alexander A Kolykhalov, Huw M L Davies, Eric J Sorscher","doi":"10.1038/s44386-025-00026-1","DOIUrl":"10.1038/s44386-025-00026-1","url":null,"abstract":"Pharmacologic activation of the cystic fibrosis transmembrane conductance regulator (CFTR) has transformed cystic fibrosis (CF) therapy. Other, more common airway diseases can also be associated with CFTR deficiency. For example, individuals with one dysfunctional CFTR variant (i.e., CF carriers), as well as those with acquired CFTR deficiency, are predisposed to both non-CF bronchiectasis and chronic rhinosinusitis, raising the possibility that CFTR stimulation in these settings could provide clinical improvement. This study describes a new triazolo-thiadiazine-based compound series optimized to augment mutant and wildtype CFTR function when administered topically to airway epithelium. Mechanism of action appears attributable-at least in part-to phosphodiesterase 4 inhibition (PDE4i), with effects on other PDEs also noted. Together with a growing body of previous and emerging evidence, our results suggest a novel therapeutic strategy for treating people with CF (PwCF) who lack access to effective modulator therapy-and addressing common diseases such as chronic bronchiectasis and rhinosinusitis in the non-CF population.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364776","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}

引用次数: 0

Mechanisms that matter: unbiased cellular screening for degraders. 重要的机制：对降解物进行无偏见的细胞筛选。

NPJ drug discovery Pub Date : 2025-10-17 DOI: 10.1038/s44386-025-00028-z

Helen E Burston, Elizabeth M Rosethorne, Francesca Cavallo, Allan Jordan, Prasamit S Baruah, Denise Swift, Roland Hjerpe

引用次数: 0

Integrating artificial intelligence into small molecule development for precision cancer immunomodulation therapy. 将人工智能整合到小分子开发中，用于精准的癌症免疫调节治疗。

NPJ drug discovery Pub Date : 2025-10-01 DOI: 10.1038/s44386-025-00029-y

Henry Sutanto, Deasy Fetarayani

引用次数: 0

Challenges and opportunities in computational studies for lipid nanoparticle development. 脂质纳米颗粒开发计算研究中的挑战和机遇。

NPJ drug discovery Pub Date : 2025-09-01 DOI: 10.1038/s44386-025-00024-3

Younghoon Oh, Sean K Bedingfield, Severin T Schneebeli, Jianing Li, Arezoo M Ardekani, Kyle J Colston, Scott P Brown

引用次数: 0

Therapeutic safety implications of SARM1 active site inhibitors: subinhibitory concentrations cause neurodegeneration. SARM1活性位点抑制剂的治疗安全性：亚抑制浓度导致神经退行性变。

NPJ drug discovery Pub Date : 2025-08-25 DOI: 10.1038/s44386-025-00023-4

Rebecca R Leahey, Martin Weber, Chang Hoon Cho, Seong Kwon Hur, Amber Cramer, Karla Manzanares, Brett Babin, Gladys Boenig, Taylor Kring, Liling Liu, Yusi Cui, Anjani Ganti, John P Evans, Marika Nespi, Justin Ly, Alicia A Nugent, Samantha A Green, Bryan K Chan, Casper C Hoogenraad, Anton Delwig, Flora I Hinz

引用次数: 0