Linker structures are a crucial component of proteolysis-targeting chimeras (PROTACs) and have traditionally been designed based on empirical methods, which presents significant challenges in the development of PROTACs. Current optimization strategies typically focus on reducing the number of rotatable bonds in the linker to limit conformational freedom. However, this approach overlooks the complexity of the target protein degradation process. Retrospective analyses suggest that merely adjusting the rotatable bonds in the linker is insufficient to control the conformational freedom of the PROTACs, indicating the need for new optimization strategies. By integration of computational methods such as molecular dynamics simulations, this study investigates the role of the linker throughout the induction process, particularly its impact on the formation and stability of the ternary complex. This approach offers potential for overcoming the limitations of traditional strategies, reducing reliance on empirical methods, and enhancing the overall efficiency and effectiveness of PROTAC design.

Peptides, valued for their high affinity and selectivity yet hindered by suboptimal pharmacokinetics, are important entry points for lead discovery; the canonical strategy preserves their key binding interactions and prunes them into developable small molecules. However, pharmacophore-based simplification methods heavily depend on high-quality databases and expert knowledge, and pocket-conditioned generation alone struggles to align critical pharmacophores and orientations, limiting the controllability and efficiency. We therefore introduce EDWARD, a geometry-pharmacophore joint framework that learns "pharmacophore cloud clusters" and radial-directional constraints from peptide-protein complexes, and performs geometry-first assembly of modular fragments and multianchor scaffolds, thereby avoiding end-to-end scaffold learning. This strategy stably maintains alignment and pocket compatibility across conformations, lengths, and topologies; achieves a better balance among affinity retention, drug-likeness, and diversity; and requires little annotation with controllable computational cost, providing a supplementary route from peptide cues to translatable small molecules.

ObjectiveWe aimed to analyze and compare the personal characteristics of undergraduate freshmen enrolled in clinical pharmacy across colleges and universities in southwest China. The goal was to delineate the current composition of the freshmen cohort and offer insights for targeted teaching strategies.MethodsFrom January 2024 to February 2024, a questionnaire survey was conducted among first-year undergraduate students majoring in clinical pharmacy in eight universities in the Sichuan Province, Yunnan Province, Guizhou Province, and Chongqing City, China. The survey covered basic information and various scales.ResultsOverall, 535 first-year undergraduate students, majoring in clinical pharmacy, completed the survey. Significant regional differences in personal characteristics existed (p < 0.05). While the respondents had similar personality traits, differences existed in their achievement goals, motivations, interests, and expectations (p < 0.05).ConclusionThis study provides suggestions for optimizing training programs to improve the education quality in clinical pharmacy, students’ practical abilities, and career expectations. Moreover, it offers valuable insights for refining training strategies and educational practices in clinical pharmacy, laying a solid foundation for the cultivation of future professional personnel.

BackgroundStudies on the application of decentralized clinical trials (DCTs) in China are limited. This study aimed to investigate the knowledge, practices, and attitudes of clinical trial practitioners in China toward DCTs.MethodAn anonymous cross-sectional study was conducted from November 1st to November 30th, 2023. A total of 621 valid questionnaires were collected, including 227 completed by Clinical Research Associates (CRAs), 150 by Clinical Research Coordinators (CRCs), and 244 by Program Managers (PMs).ResultsThe majority of respondents possessed basic knowledge of DCTs and showed a high willingness to participate, but their practice experience was limited, with a relatively high level of practice experience in internet recruitment. Respondents were more interested in the improvement of patients’ rights brought by DCTs, such as more opportunities for clinical trials. Technical barriers and data reliability were the main barriers to implementation.ConclusionClinical trial practitioners need to enhance their technical skills and knowledge about DCTs, enhance the overall level of the industry, and promote the better implementation and application of DCTs in China.

Diabetes mellitus is one of the most common chronic diseases, and blood glucose monitoring benefits for diagnosis and management of diabetic mellitus. In this paper, a multimodal photoluminescence (PL) bio-platform, R-CDs/B2O3, with solid-state fluorescence, was developed by dispersing Rhodamine B carbon dots (R-CDs) in the matrix of boric acid (BA) as a simple, cheap agent for the visual assay of intracellular and serum glucose concentration, which was based on BA can specially bound with 1, 2-diol of glucose. The good linear relationship between the PL spectra of the R-CDs/B2O3 and glucose concentration indicated that R-CDs/B2O3 could dynamically monitor glucose concentration in vitro. Furthermore, the fluorescent color variations of R-CDs/B2O3 gel were monitored by the UV lamp and the green channel intensities of the colored images were processed by using the RGB option of a smartphone, manifesting that R-CDs/B2O3 could be used as a portable test gel for serum glucose. Significantly, it is convenient for self-monitoring of blood glucose for diabetic patients. The method was also successfully used for the assay of glucose in blood serum. Hence, the proposed fluorescence sensor opens the door for further research and development of more reliable non-enzymatic assays for continuous glucose monitoring systems.

Combination of cyclin‐dependent kinases (CDKs) and histone deacetylases (HDACs) inhibitors may have statistical synergy in suppressing cancer cell proliferation. Herein, a novel CDKs/HDACs dual inhibitor T‐17 was rationally designed, synthesized, and evaluated. Our results demonstrated that T‐17 concurrently exhibited potent and balanced inhibitory activity against CDKs (IC50 = 18.0 nM) and HDACs (IC50 = 6.6 nM) and also displayed good cell viability inhibitory effect on four cancer cell lines. Meanwhile, T‐17 blocked the MDA‐MB‐231 and A549 cell cycle at G1 phase and S phase, respectively. In addition, T‐17 induced MDA‐MB‐231 cells apoptosis and inhibited the HDACs and CDKs mediated signaling pathways. Finally, we also found that T‐17 had good antitumor activity in vivo. In summary, these results indicated that T‐17 would be a promising lead compound which deserves further research.

Considering that intravascular reactive oxygen species (ROS) and inflammation are two characteristic features of the atherosclerotic microenvironment, developing an appropriate strategy to treat atherosclerosis by synergistically regulating ROS and inflammation has attracted widespread attention. Herein, a special molecule, zoledronic acid, containing imidazole and bisphosphonate groups, was selected for the first time to assist the assembly of cerium ions and produce functionalized ceria-zoledronic acid nanocomposites (CZ NCs). It not only serves as a new carrier for different kinds of drugs (e.g. probucol, PB) but also exerts an efficient multienzyme activity to achieve collaborative therapy. More importantly, platelet membrane-coated biomimetic nanoplatform (PCZ@PB NCs) specifically accumulate at inflammatory atherosclerotic lesions, synergistically regulate ROS levels and inflammation, and efficiently inhibit foam cell formation. This novel assembly method can also be applied in the treatment of many other diseases associated with oxidative stress and inflammation.

The poor penetration of nanomaterials in solid tumours and difficulty in monitoring their penetration depth are major obstacles in their application for the treatment of solid tumours. Herein, pH-responsive carbon dots (ZCD) based on a zeolitic imidazolate framework (ZIF-8) were fabricated to achieve the deep delivery of the chemotherapeutic doxorubicin (DOX) via a hierarchical size/charge dual-transformation and transcytosis. The as-prepared ZCD accumulated in the solid tumour and the acidic tumour microenvironment further triggered its decomposition. Firstly, ZCD was decomposed by the weakly acidic extracellular microenvironment of the solid tumour, enabling it to transform into small and neutrally charged particles. Subsequently, these particles were endocytosed by lysosomes, and further disintegrated into smaller and positively charged particles, which could target the Golgi apparatus. Consequently, ZCD delivered DOX deep into the solid tumour via a size-shrinking strategy and Golgi-mediated transcytosis, thus significantly improving its antitumour efficacy. In addition, carbonization endowed ZCD with superior fluorescence property, which was enhanced in the acidic microenvironment, thus improving the sensitivity and accuracy of ex vivo monitoring of the penetration depth of the nanomedicine in real time. Collectively, our results confirmed that the carbon dots obtained via the direct carbonization of ZIF-8 simultaneously exhibited enhanced deep penetration into solid tumours and fluorescence, which could be monitored, and that the carbonization of functional materials is effective to enhance their fluorescence, and further broaden their applications.

Backgrond: Astragaloside IV (AST) and metoprolol are often used together to treat cardiovascular diseases, while the herb-drug interaction (HDI) between them is still unclear. Objective: This study investigates the effect of AST on the pharmacokinetics of metoprolol in rats and its mechanism to predict the HDI. Method: First, IC50 value of AST on nine CYP450 enzymes in human liver microsomes (HLMs) was determined by the cocktail method. We explored the effect of AST on the pharmacokinetics of metoprolol (metabolized by CYP2D6) in vivo. Twelve male SD rats were equally divided into two groups, with or without pretreatment of AST (3 mg/kg/day) for 7 days, and they received metoprolol (27 mg/kg) by oral administration. Blood samples were determined using HPLC. Finally, the mechanism of AST was explored. Results: AST exhibited a moderate inhibitory effect on CYP2D6 with IC50 value of 32.28 mu M. The pharmacokinetic parameters of metoprolol were significantly altered by AST with the increase of AUC(0-infinity) (538.81 +/- 51.41 to 1088.34 +/- 86.46 mu g*min/mL, P<0.05) and C-max (6.21 +/- 0.56 to 8.34 +/- 0.87 mu g/ml, P<0.05). The investigation of the mechanism showed AST to be an irreversible inhibitor of CYP2D6 with K-I value of 2.9 mu M and K-inact of 0.018 min(-1), respectively. Conclusion: AST was found to increase the plasma exposure of metoprolol in rats. AST reduced the metabolism of metoprolol by inhibiting CYP2D6 activity. The HDI might enhance when metoprolol and AST will be applied in combination.

The poor penetration into solid tumor of nanomedicine hinders its antitumor efficacy, while the undetectability limits the monitoring of its penetration depth. In situ reducing nanoparticles’ size and introducing fluorescence property could be effective strategies solving these problems. Herein, a multifunctional carbon dot (ZCD) with pH-responsive size-shrink and fluorescence enhancement is firstly fabricated by direct carbonization of metal-organic frameworks (ZIF-8) to achieve the goals of delivery, deep-tumor penetration and penetration depth monitoring of loaded drugs. The retained drug loading capacity and pH-responsiveness of ZIF-8 lends ZCD to efficiently load antitumor drug doxorubicin (DOX) and to disintegrate into smaller particles for releasing and delivering the loaded DOX into deeper tumor, which was confirmed by the 3D tumor spheroids experiments. Moreover, the colocalization of decomposed ZCD with Golgi apparatus indicates that Golgi-mediated transcytosis may be involved in the deep penetration. In addition, carbonization gives ZCD superior fluorescence properties, and the cellular uptake assay demonstrates the fluorescence of ZCD enhances under acidic condition, especially pH 5.0, which improves the sensitivity and accuracy of monitoring the penetration depth of nanomedicine ex vivo. Collectively, direct carbonization of MOF could be a promising strategy to provide a potential paradigm for the theranostics of tumors.

Tumor microenvironment (TME) is intently related to tumor growth, progression and invasion, leading to drug resistance and insufficient therapeutic efficacy. However, remodeling TME and utilizing TME for exploring intelligent nanomaterials that can realize tumor theranostic is still challenging. Nowadays, the theranostic based on chemotherapy exposes some deficiencies, such as low targeting, weak permeability and premature clearance. Furthermore, it is challenging to cure drug-resistant tumors effectively. For the sake of solving these problems, a biomimetic decomposable nano-theranostic (MMV-Au-CDs-DOX) was well-established in this work. The Au-CDs are coated with macrophage-derived microvesicle to realize drug release accurately and enhance the biocompatibility of internal nanoparticles. Furthermore, MMV-Au-CDs-DOX would locate in the inflammation position of tumor, and disintegrate correspondingly into pieces with certain different functions stimulated by TME. Subsequently, the released anti-tumor nanodrugs were used for multimodal therapy, including chemotherapy and hemodynamic therapy. In addition, combined with the ability of Au-CDs to recognize GSH specifically, the off-on fluorescent probe was constructed to monitor the GSH of tumor cells and provided information on chemotherapy resistance.

Background Rare diseases have been increasingly recognized as unmet medical and health needs worldwide; a growing demand for the development of orphan drugs emerges subsequently. Therefore, it is of great interest for both the Chinese regulatory agency and pharmaceutical companies to keep tract on the clinical development of orphan drugs in China. Objective and method This study aims to reveal the current situation and trend of the clinical development of orphan drugs in China, based on the data collected from the Chinese official platform, dating from January 1, 2013 to December 31, 2021. Results A total of 331 clinical trials for orphan drugs were extracted from the platform, covering 31 rare diseases and 124 drugs. Increases were seen in the annual number of clinical trials and drugs being tested, with a sharp increase after 2018. About the disease types of the 331 trials, Parkinson disease (young-onset, early-onset) (86, 26%), hemophilia (70, 21%), homozygote hypercholesterolemia (60, 18%) were the most common. Furthermore, it was also observed that the largest number of clinical trial units for rare disease in east China (90, 41%) and the smallest number located in northwest China (18, 6%) and northeast China (18, 6%). Conclusions The growth trends illustrate the progress in clinical trial and drug development of rare diseases from 2013 to 2021. However, promoting orphan drugs development still is an important issue in China; at the same time, further efforts should be made for meet the unmet needs of disease types and balance the uneven distribution of medical resources for clinical trial on rare diseases.

目的 评价我国CRA和CRC的执业现状与态度,并基于CRA与CRC进行比较.方法 采用匿名的横断面在线调查,共收集1308份有效调查问卷(包括625名CRA和683名CRC).结果与结论 被调查CRA和CRC工作量都在正常范围,CRA的工作时间比CRC更长,休假时间更短,年收入也更高.被调查CRA和CRC的身体健康情况较好,锻炼频率较低,普遍存在不同程度抑郁和焦虑情绪.被调查CRA/CRC的工作满意度低于职业满意度,离开目前公司的倾向高于改变目前职业的倾向,对于临床试验行业的执业环境满意度最低.被调查CRA/CRC对其职业和行业的未来发展普遍充满信心,但是对行业发展大趋势的认知还有待加强.本研究结果可为政策制定者以及临床试验管理者提供参考,以制定改善临床试验行业从业人员执业环境和工作满意度的策略和制度.

目的 评价公众的临床试验的认知、实践与态度.方法 采用匿名的横断面在线调查,共收集702份18岁以上中国公众的有效调查问卷.结果 在702名被调查者中,有84.2％听说过临床试验,但是仅有6.0％作为受试者参与过药物临床试验.83.6％的被调查者知道"受试者的隐私和个人信息应该得到充分保护",仅48.4％的被调查者知道"患者也可以参与设计和发起符合自己需要的临床试验".41.7％的被调查者"愿意作为志愿者参加临床试验".回归分析表明"工作/专业领域""是否作为受试者参与过药物临床试验""是否有亲人朋友作为受试者参与过药物临床试验"是影响公众参与临床试验意愿的显著因素.结论 公众对临床试验的认知程度尚可,但是对于以患者为中心的临床试验发展趋势认识较低.公众的临床试验参与意愿较低,并且受自身专业背景以及相关经历影响很大.有必要开展针对公众的临床试验科普活动,积极发展临床试验公益团体,提升公众临床试验认知水平和参与积极度.

Combination of anaplastic lymphoma kinase (ALK) inhibitor with histone deacetylases (HDAC) inhibitor could exert synergistically anti-proliferative effects on ALK positive non-small cell lung cancer (NSCLC) naïve or resistant cells. In this work, we designed and synthesized a series of 2,4-pyrimidinediamine derivatives as dual ALK and HDAC inhibitors based on pharmacophore merged strategy. Among which, compound 10f displayed the most potent and balanced inhibitory activity against ALK (IC50 = 2.1 nM) and HDAC1 (IC50 = 7.9 nM), respectively. In particular, 10f was also potent against the frequently observed Crizotinib-resistant ALKL1196M (IC50 = 1.7 nM) as well as the Ceritinib-resistant ALKG1202R (IC50 = 0.4 nM) mutants. In antiproliferative activity assay, 10f exhibited impressive activity on ALK-addicted cancer cell lines at low micromole concentrations, which was comparable to that of Crizotinib and Ceritinib. Further flow cytometric analysis indicated that 10f could effectively induce cell death via cell apoptosis and cell cycle arrest. Taken together, these results suggested 10f would be a promising lead compound for the ALK-positive NSCLC treatment, especially the Ceritinib- or Crizotinib-resistant NSCLC.

Objective To develop a liquid chromatography with tandem mass spectrometry (LC-MS/MS) to simultaneously detect the activities of 9 CYP450 enzymes in human liver microsomes in order to anticipate the possibility of drug-drug interactions. Methods Nine different enzyme substrates were used as probes to incubate with human liver microsomes, with nifedipine as internal standard. All metabolites were eluted by Agilent 1290 series liquid chromatograph and then analyzed under multiple reaction monitoring. The IC50 values obtained by single substrate method and cocktail mixed substrate method were compared. Results Our established method had good specificity, and all the chromatographic peaks were completely separated without interference. The linear relationship was good. The correlation coefficients of 9 metabolites within the range of the standard curve were all greater than 0.99. The accuracy of the method was 85.34%~113.89%, the intra-day relative standard deviation (RSD) was < 12.49%, and the inter-day RSD was < 14.98%, which complied with the relevant standards. The IC50 value of the inhibitor determined by this cocktail method was highly correlated with that of a single probe substrate (R2> 0.997 8). Conclusion Our LC-MS/MS method can quickly and simultaneously measure the activities of 9 CYP450 enzymes in human liver microsomes.

Nitric oxide (NO) is a short-lived, bioactive gas that has been found to have affinitive effects on cardiovascular diseases as well as cancer biology, while NO deficiency may cause serious pathological responses. The existing chemically-synthesized NO donors have inevitable systemic toxicity and cannot be released adaptively. Hence, L-arginine, an endogenous NO precursor, merits investigation as a natural efficient NO donor. Herein, we designed amino acid-doped L-arginine CDs-based bioenzyme-responsive NO donors, which could adaptively replenish NO/ONOO- in response to different microenvironments. Our results indicated the mechanism of the NO/ONOO- supplementation of L-arginine-based CDs and their potential for nonpharmaceutical gas-involving theranostics for the first time.

借助Discovery Studio软件,以3D和2D图形的方式直观展示ATP敏感钾离子通道、雌激素受体等生物大分子的空间结构,对接模拟格列本脲等药物与相关靶点间的作用方式,进而对药物的结构特征或构效关系进行"可视化"解释,帮助学生更好地理解掌握药物化学课程中的重难点内容.

As a γ-aminobutyric acid A receptor (GABAAR) inhibitor, etomidate fulfills several characteristics of an ideal anesthetic agent, such as rapid onset with rapid clearance and high potency, along with cardiovascular stability. Unfortunately, etomidate has been reported to inhibit CYP11B1 at hypnotic doses, which is associated with a marked increase in patient deaths due to this unexpected off-target effect. In this study, molecular docking was used to simulate the binding mode of etomidate with GABAAR and CYP11B1. Based on the in-depth analysis of the binding mode, strong electron-withdrawing group on the C4 position of the imidazole ring was introduced to reduce the charge density of the nitrogen, which is beneficial in reducing the coordination bond between the imidazole nitrogen and heme iron in CYP11B1, as well as in reducing the adrenocortical suppression. Based on the results of ADMET property prediction, MEP analysis, and molecular docking simulation, 4-fluoroetomidate (EL-0052) was designed and synthesized. In vivo studies in rats and mice confirmed that EL-0052 had the efficacy similar to etomidate, but without adrenocortical suppression. These findings suggested that EL-0052 was superior to etomidate and support the continued development of EL-0052 as a preclinical candidate as an anesthetic.

对某医科大学药学生进行调查研究,对不同家庭经济状况学生的家庭背景、消费水平、在校表现等进行比较研究.调查显示,农村户口或在农村成长、父母职业层级处于底层的学生中,家庭经济困难学生的比例更高;因病致贫是家庭经济困难的最主要原因;家庭经济困难学生在生活费和社交花费上明显低于非家庭经济困难学生;而在担任学生干部、获得奖学金、成绩排名以及发展规划等方面,不同家庭经济状况学生之间没有显著差异.总体而言,学生资助工作成效显著;建议加强精准资助力度,注重济困和育人相结合,进一步提升资助成效.