靶向蛋白非催化功能的药物开发新策略

靶向蛋白催化功能的小分子抑制剂具有特异性差和临床副作用多等缺点,靶向蛋白的非催化功能在药物开发中具有较大的潜力。鉴于靶向蛋白非催化功能抑制剂的广阔的应用前景,对靶向蛋白非催化功能的抑制剂开发新策略即非催化功能结构域策略、变构调控策略和蛋白-蛋白相互作用策略进行总结,同时对其存在的问题和应用前景进行展望,以期为靶向蛋白非催化功能的药物开发提供方向。     

142份抗肿瘤药物说明书用药信息标注情况调查与分析

目的 分析抗肿瘤药物说明书用药信息标注情况,为药品说明书规范化及临床合理用药提供参考。方法 收集现行抗肿瘤药物的药品说明书,按《药品说明书和标签管理规定》和《化学药品和治疗用生物制品说明书规范细则》,统计抗肿瘤药物说明书中常见问题,及说明书各项信息的标注情况,比较同一品种、同一剂型不同厂家的抗肿瘤药物说明书信息标注差异,统计注射用抗肿瘤药物的静脉溶液配制信息标注情况。结果 共收集抗肿瘤药物说明书142份,其中国产药物99份(口服剂35份,注射剂64份),进口药物43份(口服剂28份,注射剂15份);存在的主要问题有标注信息内容前后矛盾、文字表达不清、部分项目内容简单、汉字错误、项目缺失;进口抗肿瘤药物各项用药信息的标注率高于国产抗肿瘤药物;35组同一品种和剂型但不同厂家的药物,其说明书信息标注在适应证范围、药品不良反应、注意事项、特殊人群用药、药物相互作用及药物过量等方面存在一定差异。多数静脉注射剂溶液配制信息仅标注了推荐剂量和滴注时间,缺溶剂选择、配制浓度和注意事项,进口静脉注射剂溶液配制信息比国产注射剂完整。结论 抗肿瘤药物说明书用药信息标注存在较多问题,尤其是国产抗肿瘤药物说明书的规范化程度有待提高,国家和企业应高度重视,以促进和保障临床安全用药。     

The Evolving Role of Drug Metabolism in Drug Discovery and Development

Drug metabolism in pharmaceutical research has traditionally focused on the well-defined aspects of absorption, distribution, metabolism and excretion, commonly-referred to ADME properties of a compound, particularly in the areas of metabolite identification, identification of drug metabolizing enzymes (DMEs) and associated metabolic pathways, and reaction mechanisms. This traditional emphasis was in part due to the limited scope of understanding and the unavailability of in vitro and in vivo tools with which to evaluate more complex properties and processes. However, advances over the past decade in separate but related fields such as pharmacogenetics, pharmacogenomics and drug transporters, have dramatically shifted the drug metabolism paradigm. For example, knowledge of the genetics and genomics of DMEs allows us to better understand and predict enzyme regulation and its effects on exogenous (pharmacokinetics) and endogenous pathways as well as biochemical processes (pharmacology). Advances in the transporter area have provided unprecedented insights into the role of transporter proteins in absorption, distribution, metabolism and excretion of drugs and their consequences with respect to clinical drug–drug and drug–endogenous substance interactions, toxicity and interindividual variability in pharmacokinetics. It is therefore essential that individuals involved in modern pharmaceutical research embrace a fully integrated approach and understanding of drug metabolism as is currently practiced. The intent of this review is to reexamine drug metabolism with respect to the traditional as well as current practices, with particular emphasis on the critical aspects of integrating chemistry and biology in the interpretation and application of metabolism data in pharmaceutical research.     

Anti-Cancer Drug Discovery and Development Summit

The 5th Annual Anti-Cancer Drug Discovery and Development Summit brought together an international group of academic and industry scientists to discuss recent therapeutic developments in the field of oncology. The focus of the meeting was novel targeted approaches, i.e., those agents directed against targets that are overexpressed or overactive in tumour cells. It was acknowledged that cytotoxic agents will continue to play a key role in the treatment of cancer and new developments in this area were also discussed. With over 400 anticancer drugs in clinical development and a number of recent registrations, there is great optimism that significant therapeutic advances can be made.     

Toxicogenomics in Drug Discovery and Drug Development: Potential Applications and Future Challenges

Abstract Despite the massive investments made by pharmaceutical companies on drug research and development, the number of new drug approvals has remained stagnant in the past decades. It is well known that developing safe and effective new drugs is a long, difficult, and expensive process. While the cost of developing new drugs is increasing rapidly, withdrawals of drugs from the marketplace due to adverse drug reactions (ADR) and/or toxicity is increasing concurrently. The recent advent of high-throughput in silico (computer softwares) and in vitro (cell cultures) screenings have somewhat alleviated some, but not all, of these challenges by providing an efficient and effective way for developing safer and better drugs. This emerging technology, known as toxicogenomics, has great potential to facilitate the development of methodologies that could predict the long-term toxic effects of compounds using relatively short-term bioassays. This review is aimed at discussing the potential applications and future challenges of toxicogenomics in drug discovery and drug development.     

Mass Spectrometry Innovations in Drug Discovery and Development

This review highlights the many roles mass spectrometry plays in the discovery and development of new therapeutics by both the pharmaceutical and the biotechnology industries. Innovations in mass spectrometer source design, improvements to mass accuracy, and implementation of computer-controlled automation have accelerated the purification and characterization of compounds derived from combinatorial libraries, as well as the throughput of pharmacokinetics studies. The use of accelerator mass spectrometry, chemical reaction interface-mass spectrometry and continuous flow-isotope ratio mass spectrometry are promising alternatives for conducting mass balance studies in man. To meet the technical challenges of proteomics, discovery groups in biotechnology companies have led the way to development of instruments with greater sensitivity and mass accuracy (e.g., MALDI-TOF, ESI-Q-TOF, Ion Trap), the miniaturization of separation techniques and ion sources (e.g., capillary HPLC and nanospray), and the utilization of bioinformatics. Affinity-based methods coupled to mass spectrometry are allowing rapid and selective identification of both synthetic and biological molecules. With decreasing instrument cost and size and increasing reliability, mass spectrometers are penetrating both the manufacturing and the quality control arenas. The next generation of technologies to simplify the investigation of the complex fate of novel pharmaceutical entities in vitro and in vivo will be chip-based approaches coupled with mass spectrometry.     

Protein Binding of Phenprocoumon in the Absence and Presence of Furosemide

Abstract A modification of a fluorometric assay for phenprocoumon is described. The sensitivity of the method has been increased so that the lower limit is 5 ng/ml. By an ultrafiltration technique, phenprocoumon (PPC), in therapeutic concentrations, was bound to the extent of 99.9%, both in undiluted plasma and in Krebs–Henseleit (K–H) solutions containing 4 g human serum albumin (HSA)/100 ml. An increase in the pH from 6.05 to 8.02 in phosphate buffers containing 0.2 g HSA/100 ml yielded an increase in the apparent association constant for PPC binding to HSA from 0.562–10⁶ 1/mol to 1.195–10⁶1/mol, while the number of PPC mol bound per mol albumin remain unchainged (1.05 and 1.03 respectively). A reduced binding of PPC in undiluted plasma containing increasing concentrations of furosemide have been observed. Scatchard plots based on binding studies in K–H solutions containing 0.2 g HSA/100 ml indicate a competitive nature of the albumin binding of PPC and furosemide.     

Pokeweed Antiviral Protein: Its Cytotoxicity Mechanism and Applications in Plant Disease Resistance

Pokeweed antiviral protein (PAP) is a 29 kDa type I ribosome inactivating protein (RIP) found in pokeweed plants. Pokeweed produces different forms of PAP. This review focuses on the spring form of PAP isolated from Phytolacca americana leaves. PAP exerts its cytotoxicity by removing a specific adenine from the α-sarcin/ricin loop of the large ribosomal RNA. Besides depurination of the rRNA, PAP has additional activities that contribute to its cytotoxicity. The mechanism of PAP cytotoxicity is summarized based on evidence from the analysis of transgenic plants and the yeast model system. PAP was initially found to be anti-viral when it was co-inoculated with plant viruses onto plants. Transgenic plants expressing PAP and non-toxic PAP mutants have displayed broad-spectrum resistance to both viral and fungal infection. The mechanism of PAP-induced disease resistance in transgenic plants is summarized.     

治疗药物监测系统的开发及其在回顾性分析中的应用

目的:为临床药学工作者提供可自动进行多功能回顾性分析、查询及输入数据简便的治疗药物监测系统(TDMS程序)。方法:TDMS程序用VISUAL BASIC 5.0开发,在Windows 95操作系统上运行;对我院1997、1998两年用荧光偏振免疫法所测定血药浓度数据运用TDMS程序分析。结果:TDMS程序可自动增添病人档案、自动给出血药浓度参考值、能进行有效血药浓度范围情况分析、血药浓度次数比较、病人血药浓度的统计数据等回顾性分析及多功能查询。结论:TDMS程序是开展治疗药物监测(TDM)工作非常实用的工具,我院医生对TDM的依从性正逐渐增强。     

深度学习在药物研发中的研究进展

近年来以深度学习为代表的人工智能技术与医学、药学等多个领域深度融合。深度学习被应用于蛋白质结构与功能预测、药物靶点预测、药物代谢动力学性质预测、药物有效性及安全性预测以及药物相互作用预测等多个药物研发环节,取得了显著成就,提高研发效率的同时降低临床前试验以及临床试验相关的成本和风险。通过总结多种深度学习方法在药物研发各个过程中的具体应用及分析不同深度学习方法在药物研发中的应用特点,阐述了深度学习在药物研发中现存的一些问题并做出展望,以期为进一步研究提供借鉴的思路和方法。     

人工智能在药物发现中的应用与挑战

新药研发存在周期长、费用高和成功率低等特点。人工智能技术是近些年来的热点技术之一,在很多领域都有非常广泛的应用,多种人工智能方法已经成功应用于药物的发现过程。综述总结了常用机器学习方法和深度学习方法在药物研发领域中的应用,同时也提出了人工智能存在的问题和面临的挑战。整体而言,人工智能技术在药物研发领域发展潜力巨大,将为医药发展带来新的机遇和希望。     

Probing Secondary Glutaminyl Cyclase (QC) Inhibitor Interactions Applying an in silico‐Modeling/Site‐Directed Mutagenesis Approach: Implications for Drug Development

Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate‐modified amyloid peptides deposited in neurodegenerative disorders such as Alzheimer’s disease. Inhibitors of QC are currently in development as potential therapeutics. The crystal structures of the potent inhibitor PBD150 bound to human and murine QC (hQC, mQC) have been described recently. The binding modes of a dimethoxyphenyl moiety of the inhibitor are significantly different between the structures, which contrasts with a similar K_i value. We show the conformation of PBD150 prone to disturbance by protein–protein interactions within the crystals. Semi‐empirical calculations of the enzyme–inhibitor interaction within the crystal suggest significant differences in the dissociation constants between the binding modes. To probe for interactions in solution, a site‐directed mutagenesis on hQC was performed. The replacement of F325 and I303 by alanine or asparagine resulted in a 800‐fold lower activity of the inhibitor, whereas the exchange of S323 by alanine or valine led to a 20‐fold higher activity of PBD150. The results provide an example of deciphering the interaction mode between a target enzyme and lead substance in solution, if co‐crystallization does not mirror such interactions properly. Thus, the study might provide implications for rapid screening of binding modes also for other drug targets.     

降压药物干预下高血压前期的血尿酸、C-反应蛋白变化

目的通过对高血压前期的降压药物干预,观察血尿酸(UA)、C-反应蛋白(CRP)的变化,探索血尿酸、C-反应蛋白与高血压前期的相关性及对高血压前期降压药物干预的必要性。方法入选2007年至2009年我院门诊体检符合高血压前期人群共238例,随机分成A组(安慰剂组)114例,B组(降压药物干预组)124例,对A、B组均监测血压3年,其中A组给予安慰剂,对B组前1年半予厄贝沙坦降压治疗,后1年半也给予安慰剂,A、B组同时观察血压、血尿酸、C-反应蛋白的变化。结果 A组88例发展为高血压,血尿酸、C-反应蛋白进行性升高,B组前1年半仅有11例发展为高血压,血尿酸、C-反应蛋白与治疗前比较无明显升高,后1年半B组共有93例发展为高血压,血尿酸、C-反应蛋白较前也明显升高,与A组比较无统计差异。结论血尿酸、C-反应蛋白与血压独立相关,对高血压前期人群应尽早予以降压药物干预,以降低高血压的发生率及控制心脑血管病的危险因素,从而减少心脑血管疾病的发生、发展。     

金纳米粒及其在药物传递系统中的应用研究进展

近年来,随着纳米材料科学的蓬勃发展,金纳米粒由于具有独特的光学和物理性质以及毒性小、比表面积大、表面可功能化修饰、易与药物分子结合等特点,其作为载体在药物传递系统中的应用已引起广泛关注。综述金纳米粒的特性、合成方法、体内分布与毒性以及在不同药物传递系统中的应用研究。     

Steering New Drug Discovery Campaigns: Permeability, Solubility,and Physicochemical Properties in the bRo5 Chemical Space

An increasing number of drug discovery programs concern compounds in the beyond rule of 5 (bRo5) chemical space, such as cyclic peptides, macrocycles, and degraders. Recent results show that common paradigms of property-based drug design need revision to be applied to larger and more flexible compounds. A virtual event entitled “Solubility, permeability and physico-chemical properties in the bRo5 chemical space” was organized to provide preliminary guidance on how to make the discovery of oral drugs in the bRo5 space more effective. The four speakers emphasized the importance of the bRo5 space as a source of new oral drugs and provided examples of experimental and computational methods specifically tailored for design and optimization in this chemical space.     

人工智能在新药研发中的应用现状与挑战

人工智能作为一种新兴技术,是新药研发实现降本增效的重要方式之一,人工智能+新药研发已成为中国医药企业加速创新转型的重要驱动力。对国内外相关文献和资料进行检索和归纳,重点分析人工智能在新药研发领域的应用模式,总结开展人工智能应用的企业主体及应用场景,探究我国人工智能赋能新药研发面临的主要挑战。     

DNA芯片技术与新药的设计和开发

目的：介绍DNA芯片技术和评价其在新药设计和开发中的价值；方法：查阅和综述近年来有关文献。结果：DNA芯片技术可同时检测和分析几千种基因的表达类型，为基因的功能研究和新药开发提供线索。结论：DNA芯片有助于识别药物相应靶序列，亦可用于监视药物治疗反应的基因表达改变.     

Application of Dual Radiotelemetric Technique in Studying Drug–Drug Interaction Between Diclofenac Sodium and Ranitidine HCl in Volunteers

Drug–drug interaction between a commercial diclofenac sodium enteric-coated tablet (Voltaren; V) and a ranitidine HCI tablet (Zantac; Z) was evaluated using a dual radiotelemetric technique according to a randomized three-way Latin-Square crossover design balanced for carryover effects. V and Z were given either alone or in combination (Treatment V, Z, V/Z), with a 14-day washout period between treatments. Eighteen fasted subjects swallowed a tethered Heidelberg pH capsule to provide continuous gastric pH. Then the assigned treatment drug and another Heidelberg pH capsule were given simultaneously. The free pH capsule provided information regarding gastric residence time (GRT). Serial blood samples were obtained for up to 12 hr after dosing and drug levels were determined by validated HPLC methods. Treatment effects on AUC, C _max, T _max, T _lag, T _max–T _lag, and T _1/2 were not significant except C _max, which differed slightly for both V and Z when given in combination as compared to alone. Gastric residence times were 46, 33, and 51 min for Treatments V, Z, and V/Z, respectively. Gastric exposure of the enteric-coated tablet of diclofenac was estimated by pH values obtained from the tethered capsule. Median pH values at 3 and 15 min prior to gastric emptying were 3.8 and 4.9 for the combination treatment versus 2.1 and 2.7 for diclofenac alone. The results of this study indicated that there was minimal drug–drug interaction between diclofenac and ranitidine. The gastric pH range resulting from this study did not influence the oral absorption of enteric-coated diclofenac.