Drug discoveries & therapeutics最新文献

Daraxonrasib: The first-in-class RAS(ON) multi-selective inhibitor approved for treatment of metastatic pancreatic adenocarcinoma. Daraxonrasib：首个被批准用于治疗转移性胰腺腺癌的RAS（ON）多选择性抑制剂。

Drug discoveries & therapeutics Pub Date : 2026-09-25 DOI: 10.5582/ddt.2026.01067

Yueyi Sun, Chen Pang, Jianjun Gao

{"title":"Daraxonrasib: The first-in-class RAS(ON) multi-selective inhibitor approved for treatment of metastatic pancreatic adenocarcinoma.","authors":"Yueyi Sun, Chen Pang, Jianjun Gao","doi":"10.5582/ddt.2026.01067","DOIUrl":"https://doi.org/10.5582/ddt.2026.01067","url":null,"abstract":"Advanced pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with limited benefits from conventional chemotherapy. Daraxonrasib is an oral, noncovalent RAS(ON) multi-selective inhibitor that forms a ternary complex with cyclophilin A and GTP-bound RAS, blocking downstream signaling across multiple mutant and wild-type RAS proteins. On August 26, 2026, the US Food and Drug Administration approved daraxonrasib for adults with metastatic pancreatic adenocarcinoma previously treated with systemic therapy or ineligible for multiagent systemic therapy, without a mutation-specific restriction. In the randomized phase III RASolute 302 trial involving 500 previously treated patients with a good performance status, daraxonrasib improved median overall survival from 6.7 to 13.2 months (hazard ratio, 0.40) and progression-free survival from 3.6 to 7.2 months in the overall randomized population. Grade 3 or higher treatment-related adverse events were less frequent with daraxonrasib than chemotherapy (43.6% versus 57.5%), although one treatment-related death from pneumonitis occurred. Common toxicities included rash, diarrhea, and stomatitis. Limited follow-up and small non-G12 subgroups warrant caution regarding the generalizability of that trial's results. Acquired resistance, frequently involving RAS pathway reactivation, remains an important challenge. Ongoing studies are evaluating earlier treatment settings and combination strategies, while long-term safety and outcomes in patients with a poorer performance status require further investigation.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The conversion window in hepatocellular carcinoma: When resectability alone is not an indication for surgery. 肝细胞癌的转化窗口：当可切除性不是手术的指征时。

Drug discoveries & therapeutics Pub Date : 2026-09-25 DOI: 10.5582/ddt.2026.01068

Weiping Zhu, Lu Wang, Wei Tang

{"title":"The conversion window in hepatocellular carcinoma: When resectability alone is not an indication for surgery.","authors":"Weiping Zhu, Lu Wang, Wei Tang","doi":"10.5582/ddt.2026.01068","DOIUrl":"https://doi.org/10.5582/ddt.2026.01068","url":null,"abstract":"Effective systemic therapy has expanded the possibility of resection in hepatocellular carcinoma, while making its timing more uncertain. Technical feasibility alone cannot establish whether surgery adds value to an effective treatment sequence. In this context, the conversion window can be understood as a patient-specific interval in which achievable tumor clearance, preserved hepatic and systemic reserve, and sufficient evidence of disease control are considered together. These factors should be distinguished from the multidisciplinary team's overall determination of whether surgery is likely to provide additional benefit. Evidence from a randomized study supports consolidation in selected patients but does not define an optimal date for surgery. Retrospective associations between treatment duration and pathological response remain vulnerable to selection bias and cannot justify universal timing thresholds. Serial assessment should incorporate remnant liver function, treatment toxicity, drug interruption, uncertainty regarding residual disease, and patient preferences. Future trials and prospective registries should evaluate explicit timing strategies from the point of initial surgical eligibility, including patients who subsequently become ineligible, using survival, safety, and quality-of-life outcomes to inform individualized decisions.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bepirovirsen: The first antisense oligonucleotide approved to achieve a functional cure for chronic hepatitis B. Bepirovirsen：首个被批准用于慢性乙型肝炎功能性治愈的反义寡核苷酸。

Drug discoveries & therapeutics Pub Date : 2026-09-25 DOI: 10.5582/ddt.2026.01064

Yueyi Sun, Jianjun Gao

{"title":"Bepirovirsen: The first antisense oligonucleotide approved to achieve a functional cure for chronic hepatitis B.","authors":"Yueyi Sun, Jianjun Gao","doi":"10.5582/ddt.2026.01064","DOIUrl":"https://doi.org/10.5582/ddt.2026.01064","url":null,"abstract":"Chronic hepatitis B (CHB) remains a major global health burden despite the availability of potent nucleos(t)ide analogue (NA) therapy. Although NAs effectively suppress hepatitis B virus (HBV) DNA replication and reduce the risks of cirrhosis and hepatocellular carcinoma, they have limited effects on covalently closed circular DNA and hepatitis B surface antigen (HBsAg) production, and most patients require prolonged treatment. Bepirovirsen is an antisense oligonucleotide that targets conserved HBV RNA sequences, promotes RNase H1-mediated RNA degradation, and reduces viral antigen expression and replication. In August 2026, Japan approved bepirovirsen (Hibsago) for selected adults with chronic HBV infection receiving NA therapy, representing its first global regulatory approval. Approval was supported by the phase III B-Well 1 and B-Well 2 trials, in which a functional cure after treatment withdrawal was achieved in 20% and 19% of bepirovirsen-treated patients, respectively, versus 0% with a placebo. Response rates were higher among patients with lower baseline HBsAg levels. The overall safety profile was acceptable; however, elevated alanine aminotransferase levels were observed in 6% of bepirovirsen-treated participants. Ongoing studies will further define long-term durability, broader applicability, and optimal treatment strategies.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advances in multimodal data integration for drug efficacy prediction: Methodological evolution and clinical translation. 药物疗效预测的多模态数据整合研究进展：方法演变与临床转化。

Drug discoveries & therapeutics Pub Date : 2026-09-21 Epub Date: 2026-08-23 DOI: 10.5582/ddt.2026.01042

Jingwen Fang, Zihan Wang, Junhao Shao, Jiewei Fan, Qichao Luo

{"title":"Advances in multimodal data integration for drug efficacy prediction: Methodological evolution and clinical translation.","authors":"Jingwen Fang, Zihan Wang, Junhao Shao, Jiewei Fan, Qichao Luo","doi":"10.5582/ddt.2026.01042","DOIUrl":"10.5582/ddt.2026.01042","url":null,"abstract":"Drug efficacy prediction remains a cornerstone of drug development and precision therapy. However, integrating heterogeneous biomedical data, including multi-omics profiles, pathological imaging, electronic health records, and pharmacokinetic-pharmacodynamic (PK/PD) time-series, faces three fundamental barriers, namely cross-domain distribution shifts between preclinical and clinical data, relational mismatches between isolated vector representations and biological networks, and feature heterogeneity across disparate modalities. To address these challenges, three AI paradigms have emerged, transfer learning for cross-domain alignment, graph neural networks for structured relational modeling, and Transformers for global cross-modal feature interaction. Importantly, these techniques form a many-to-many complementary system rather than a one-to-one correspondence, a key insight that this review explicitly formalizes. We further elaborate encoding workflows for PK/PD data to bridge static molecular signatures with dynamic in vivo exposure trajectories. Four graded clinical applications are outlined, including personalized monotherapy, combination optimization, drug repurposing, and preclinical-to-clinical evaluation of novel candidates. We also dissect persistent bottlenecks such as data harmonization, model interpretability, and prospective validation, and propose five actionable directions, namely privacy-preserving benchmarks, causally interpretable models, temporal dynamic frameworks, cross-domain generalization, and lightweight clinical tools. By integrating theoretical rationales, methodological synergies, and hierarchical translational scenarios, this review provides a unified roadmap to accelerate the clinical deployment of multimodal drug response prediction.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":"280-292"},"PeriodicalIF":0.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disproportionality analysis of opioid-related urinary retention using the JADER database: Focus on the lack of signal for transdermal fentanyl. 使用JADER数据库对阿片类药物相关尿潴留进行歧化分析：重点关注透皮芬太尼缺乏信号。

Drug discoveries & therapeutics Pub Date : 2026-09-21 Epub Date: 2026-08-21 DOI: 10.5582/ddt.2026.01040

Yusuke Tanaka, Masahiko Kimura, Naohito Ide, Ken-Ichi Sako, Tomoji Maeda

{"title":"Disproportionality analysis of opioid-related urinary retention using the JADER database: Focus on the lack of signal for transdermal fentanyl.","authors":"Yusuke Tanaka, Masahiko Kimura, Naohito Ide, Ken-Ichi Sako, Tomoji Maeda","doi":"10.5582/ddt.2026.01040","DOIUrl":"10.5582/ddt.2026.01040","url":null,"abstract":"Urinary retention is a known adverse effect of opioids, but limited information is available on how this adverse event varies among individual opioids. This study evaluated disproportionality signals between major opioids and urinary retention using the Japanese Adverse Drug Event Report database (JADER). We performed a disproportionality analysis of reports submitted between April 2004 and October 2025. Signals were assessed using reporting odds ratios (RORs), 95% confidence intervals (CIs), and the Information Component (IC). Adverse events were identified using the Medical Dictionary for Regulatory Activities/Japanese version (MedDRA/J) term \"urinary retention.\" A sensitivity analysis was conducted using a broader definition of urinary dysfunction that also included \"Dysuria.\" Time to onset was calculated from the start of opioid administration to event onset, and daily doses were converted to oral morphine equivalents. Significant signals were detected for morphine, oxycodone, tramadol, and codeine. Transdermal fentanyl was the only opioid without a detectable signal, even under the broader definition of urinary dysfunction. Among opioids with detected signals and available dose information, urinary retention was reported even at relatively low morphine-equivalent doses, suggesting the need for careful monitoring at the start of opioid therapy. The absence of a signal for transdermal fentanyl may reflect a lower reporting frequency in JADER, but not a lower clinical risk, of urinary retention. Given the limitations of spontaneous reporting systems, these findings are hypothesis-generating and are insufficient to guide opioid selection or switching.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":"343-348"},"PeriodicalIF":0.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sensory testing assessment of dosage forms designed to resist overdose. 抗过量用药剂型的感官测试评估。

Drug discoveries & therapeutics Pub Date : 2026-09-21 Epub Date: 2026-08-18 DOI: 10.5582/ddt.2026.01036

Kazuki Nagashima, Rin Tanaka, Fumiya Owase, Yuko Sekine

{"title":"Sensory testing assessment of dosage forms designed to resist overdose.","authors":"Kazuki Nagashima, Rin Tanaka, Fumiya Owase, Yuko Sekine","doi":"10.5582/ddt.2026.01036","DOIUrl":"10.5582/ddt.2026.01036","url":null,"abstract":"Overdose incidence has increased among young individuals, particularly involving psychotropic and over-the-counter (OTC) drugs. However, there is limited information regarding how the physical form of medications-such as tablet size or thickness-affects the ability to take large doses. This study aims to determine which tablet characteristics (size, thickness, and volume) can discourage overdose by using sensory testing methods. The diameters and thicknesses of tablets commonly used in overdosing were measured. Additionally, dummy tablets were three-dimensionally (3D) printed, after which sensory tests were conducted to evaluate how many tablets could be comfortably consumed in large quantities, as well as the ease of consumption, rated on a 5-point scale. The respondents were students (average age: 21.3 ± 2.1 years, n = 253). Results indicate that OTC drugs typically have larger and thicker tablets compared with prescription drugs. Sensory tests of 3D-printed dummy tablets found that smaller tablets are easier to ingest in large numbers, whereas larger and thicker tablets are harder to consume in bulk. For tablets with the same diameter, a 5-mm thickness tends to make overdose more difficult compared with a 2-mm thickness. Importantly, tablets with a combined diameter and thickness of 13 mm or more and a volume of at least 190 mm3 are less likely to be overdosed. These findings can assist pharmacists in selecting appropriate dosage forms for patients at risk of overdose and provide pharmaceutical companies with guidance during product development.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":"335-342"},"PeriodicalIF":0.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nicotine administration selectively inhibits kainate-induced Arc and junB but not c-fos and egr1 mRNA expression in mouse cerebral cortex. 尼古丁可选择性抑制盐酸盐诱导的小鼠大脑皮层Arc和junB的表达，但对c-fos和egr1 mRNA的表达无抑制作用。

Drug discoveries & therapeutics Pub Date : 2026-09-21 Epub Date: 2026-08-21 DOI: 10.5582/ddt.2026.01034

Daisuke Ihara, Yuna Kato, Akiko Tabuchi

{"title":"Nicotine administration selectively inhibits kainate-induced Arc and junB but not c-fos and egr1 mRNA expression in mouse cerebral cortex.","authors":"Daisuke Ihara, Yuna Kato, Akiko Tabuchi","doi":"10.5582/ddt.2026.01034","DOIUrl":"10.5582/ddt.2026.01034","url":null,"abstract":"The nicotinic acetylcholine receptor is an ion channel receptor that is highly expressed in the brain and can cooperatively propagate several signals with other ion channel receptors in neurons. However, little is known about how nicotinic acetylcholine and kainate receptors, both of which enable cation influx into neurons, cooperatively regulate immediate early genes. In this study, we administrated both ligands, nicotine and kainate, into mice and investigated alterations of the immediate early genes activity-regulated cytoskeleton-associated protein (Arc), junB, c-fos, and egr1 in the cerebral cortex, hippocampus, olfactory bulb, and cerebellum. Kainate alone showed a tendency to induce all four immediate early genes in all four brain regions, whereas nicotine alone did not induce them strongly. However, pretreatment of nicotine before administration of kainate showed differential effects of nicotine on mRNA expression across different brain regions. Nicotine selectively inhibited kainate-induced Arc and junB mRNA expression in the cerebral cortex. These findings suggest that nicotine influences specific brain regions via the induction of certain immediate early genes.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":"329-334"},"PeriodicalIF":0.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acitretin-inspired medicinal chemistry for Alzheimer's disease: A biomarker-gated central nervous system (CNS) discovery framework. 阿曲全激发的阿尔茨海默病药物化学：生物标志物门控中枢神经系统（CNS）发现框架。

Drug discoveries & therapeutics Pub Date : 2026-09-21 Epub Date: 2026-08-18 DOI: 10.5582/ddt.2026.01054

Tian-Ge Qin, Yue Han

{"title":"Acitretin-inspired medicinal chemistry for Alzheimer's disease: A biomarker-gated central nervous system (CNS) discovery framework.","authors":"Tian-Ge Qin, Yue Han","doi":"10.5582/ddt.2026.01054","DOIUrl":"10.5582/ddt.2026.01054","url":null,"abstract":"Alzheimer's disease (AD) still lacks scalable oral strategies for early intervention. This article examines acitretin, a systemic retinoid used for severe psoriasis, as a clinically characterized scaffold for central nervous system (CNS) medicinal chemistry-not as a parent drug for direct repurposing or as a predefined candidate. Retinoic acid receptor/retinoid X receptor signaling can induce a disintegrin and metalloprotease 10 (ADAM10), the principal neuronal α-secretase of amyloid precursor protein, thereby encouraging non-amyloidogenic cleavage and soluble amyloid precursor protein-α (sAPPα) production. Supporting evidence includes mechanistic studies, murine blood-brain barrier penetration, functional observations in an amyloid mouse model, and a small randomized human study showing a short-term increase in cerebrospinal fluid sAPPα. These findings provide a human biomarker anchor but do not establish adequate unbound brain exposure, durable target engagement, clinical efficacy, or a safe chronic therapeutic window. The resulting concept is an evidence-gated scaffold-redesign strategy: future work may test whether retinoid-ADAM10-APP signaling can be retained while systemic retinoid burden and metabolite persistence are reduced. Further progression would require convergence of unbound CNS exposure, bounded sAPPα modulation, and acceptable safety within the same concentration range.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":"349-353"},"PeriodicalIF":0.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enlicitide: The first oral PCSK9 inhibitor approved for treatment of hypercholesterolemia. Enlicitide：首个被批准用于治疗高胆固醇血症的口服PCSK9抑制剂。

Drug discoveries & therapeutics Pub Date : 2026-09-21 Epub Date: 2026-08-14 DOI: 10.5582/ddt.2026.01051

Yueyi Sun, Jianjun Gao

{"title":"Enlicitide: The first oral PCSK9 inhibitor approved for treatment of hypercholesterolemia.","authors":"Yueyi Sun, Jianjun Gao","doi":"10.5582/ddt.2026.01051","DOIUrl":"10.5582/ddt.2026.01051","url":null,"abstract":"Hypercholesterolemia, and particularly elevated low-density lipoprotein cholesterol (LDL-C), is a major causal factor in atherosclerotic cardiovascular disease (ASCVD) and contributes substantially to coronary heart disease, ischemic stroke, and peripheral artery disease. Statins remain the cornerstone of lipid-lowering therapy, while ezetimibe and injectable proprotein convertase subtilisin/kexin 9 (PCSK9) targeted agents are added when further LDL-C reduction is required. However, concerns about injections, cost, accessibility, and treatment inertia have limited the use of existing PCSK9 therapies, creating a need for potent oral alternatives. Enlicitide, approved by the US Food and Drug Administration in July 2026, is the first approved oral PCSK9 inhibitor. This macrocyclic peptide blocks the interaction between circulating PCSK9 and hepatic LDL receptors, thereby increasing receptor recycling and LDL-C clearance. In the phase III CORALreef Lipids and CORALreef HeFH trials, once-daily enlicitide reduced LDL-C by approximately 60%, and the effect was maintained for up to 52 weeks. Adverse event rates were generally similar to those observed with a placebo. Nevertheless, those trials primarily evaluated LDL-C reduction rather than cardiovascular outcomes, and their duration was insufficient to establish long-term safety. The ongoing CORALreef Outcomes trial will determine whether enlicitide-mediated LDL-C reduction translates into fewer major cardiovascular events and will help define its long-term clinical role.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":"354-356"},"PeriodicalIF":0.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148766074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling the allosteric inhibition mechanism of SARS-CoV-2 main protease and discovery of a novel allosteric inhibitor. 揭示SARS-CoV-2主要蛋白酶的变构抑制机制，发现新的变构抑制剂。

Drug discoveries & therapeutics Pub Date : 2026-09-21 Epub Date: 2026-08-26 DOI: 10.5582/ddt.2026.01050

Quanling Zhang, Tingting Wen, Mengsi Li, Xiaowen Tang

{"title":"Unveiling the allosteric inhibition mechanism of SARS-CoV-2 main protease and discovery of a novel allosteric inhibitor.","authors":"Quanling Zhang, Tingting Wen, Mengsi Li, Xiaowen Tang","doi":"10.5582/ddt.2026.01050","DOIUrl":"10.5582/ddt.2026.01050","url":null,"abstract":"The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) is a crucial therapeutic target for anti-coronavirus disease 2019 (COVID-19) drug development, as it is essential for viral replication. However, mutations within the active site have compromised the efficacy of current competitive inhibitors, prompting the exploration of alternative inhibition strategies. In this study, we systematically investigated the allosteric inhibition mechanism of SARS-CoV-2 Mpro by pelitinib and leveraged this insight for new inhibitor discovery. Through extensive molecular dynamics simulations, we showed that pelitinib exerts allosteric inhibition via the L141-S144-C145-H41 interaction network: it restricts the flexibility of L141 through CH-π interactions, transmits this effect to C145 via S144, stabilizes the hydrogen bond between C145 and H41, and thereby reduces the flexibility of the S3 helix (residues 40-60). This series of conformational changes induces the contraction of the Mpro catalytic pocket from ~1200 Å³ to ~800 Å³, impairs substrate binding, and ultimately appears to impair Mpro activity. Based on this mechanism, we performed structure-based virtual screening and identified a novel compound (Cpd-1). Biological evaluations showed that Cpd-1 exhibits superior Mpro inhibitory activity compared to pelitinib, with negligible off-target binding to human EGFR and Myt1 kinase, low cytotoxicity (cell viability > 60% at 200 μM), and predicted inhibitory activity against clinically relevant Mpro-resistant mutants based on computational analysis. Our findings provide mechanistic insights into a key allosteric mechanism for Mpro inhibition but also provide a promising chemical scaffold for further development as an Mpro-targeting inhibitor.","PeriodicalId":520606,"journal":{"name":"Drug discoveries & therapeutics","volume":" ","pages":"309-321"},"PeriodicalIF":0.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0