药物开发的新策略:并联有机合成及库筛选

药物开发的新策略：并联有机合成及库筛选王德心（中国医学科学院、中国协和医科大学药物研究所北京１０００５０）近几年随着分子生物学、计算机辅助分子模型分析（ＣＡＭＭ）与药物化学的密切配合，使构效关系（ＳＡＲ）研究及合理的药物设计（ｒａｔｉｏｎａｌｄｒｕｇ...     

化学微阵列：一种药物筛选和发现的新工具

随着基因组和蛋白质组学研究发现大量药靶，高通量合成产生多种化合物库，基于微孔板的高通量筛选（HTS）术面临着严峻挑战，迫切需要发展更为快速经济的新方法。化学微阵列技术应运而生。近年来研究证明，涉及不同表面化学与活化策略的化学微阵列技术，能成功地应用于评价化合物与蛋白质之间的相互作用、酶活性的抑制、靶的识剐、信号通路机制的解析和基于细胞的功能分析之中。对于平行筛选作用于多靶的各种化合物库，该法显示了前所未有的潜力。     

QuECHERS-HPLC-MS测定人血浆中3种大环内酯类抗菌药物及其代谢物含量

目的 建立测定人血浆中3种大环内酯类抗菌药物（红霉素、地红霉素、螺旋霉素Ⅰ）及其代谢物（脱水红霉素、红霉素A烯醇醚、红霉胺、新螺旋霉素Ⅰ）的分析方法。方法 用乙腈溶液提取,QuECHERS方法净化,采用无水硫酸镁和无水乙酸钠沉淀蛋白和盐析分层,无水硫酸镁和石墨碳烯净化,上清液氮气吹干后甲醇复溶待测,用Eclipse Plus C₁₈色谱柱分离,电喷雾正离子模式,多反应离子监测扫描,内标法定量。结果 3种大环内酯类抗菌药物及其代谢物浓度在4~900 ng·mL^-1内的线性关系良好（r>0.999）,定量限<10 ng·mL^-1;在3个添加水平下,3种大环内酯类抗菌药物及其代谢物的提取回收率可达81.45%~96.82%,日内精密度<5.00%,日间精密度<10.00%。结论 QuECHERS-液相色谱串联三重四级杆质谱测定血浆中3种大环内酯类抗菌药物及其代谢物的分析方法简单,快速,灵敏,特异性强,适用于血浆中大环内酯类抗菌药物及其代谢物的测定。     

氨基糖苷类和糖肽类抗菌药物的治疗药物监测

抗菌药物治疗药物监测(TDM)是抗菌药物合理应用必不可少的一部分。氨基糖苷类和糖肽类抗菌药物的药代动力学特点亦决定其TDM的必要性,本文对其进行综述。     

液相色谱质谱联用检测药物反应性代谢物的研究进展

候选药物在体内向反应性代谢物的生物转化过程中,人们不希望其生成能共价结合大分子(如蛋白质和DNA)的反应性代谢物。作为候选药物吸收、分布、代谢和排泄(ADME)性质整体评价的一部分,许多制药公司已开始采用多种体内外筛选方法研究其是否有生成反应性代谢物的可能,并鉴定反应性代谢物的性质。发现问题化合物后,通过合适的结构修饰使潜在的生物转化减少至最低。因此,检测、鉴定和定量测定活性代谢产物在药物开发过程中非常重要。三级四极杆质谱是用于分析活性代谢产物的常规方法。在过去3年间,为改善分析灵敏度和选择性,实现高通量筛选,已发展了许多新的质谱方法。本文重点阐述在药物开发过程中应用液相色谱质谱联用(LC-MS/MS)检测和鉴定反应性代谢物的最新进展,尤其关注线性离子阱(LTQ)、混合三级四极杆-线性离子阱(Q-trap)和高分辨LTQ-静电场轨道阱的应用。     

喹诺酮类抗菌药物的抗肿瘤作用

喹诺酮类抗菌药物以4 -喹诺酮母核作为基本结构 ,对细菌DNA回旋酶具有选择性抑制作用 ,目前作为一种常用的抗菌药物广泛应用于临床。其抗菌谱广 ,对革兰阴性菌、金黄色葡萄球菌有良好的抗菌作用。近年来的研究表明 ,某些喹诺酮衍生物还具有抗肿瘤作用。1化学结构与抗肿瘤作用的关系1 1喹诺酮类药物的基本结构目前常用的喹诺酮类药物多为第3代 ,即氟喹诺酮类。它通过对喹诺酮母核化学结构的修饰出现一系列新型氟取代的4 -喹诺酮衍生物。在化学结构上 ,基本母环的3位有1个羧基 ,6位通常有氟取代 ,多数7位有1个哌嗪环 ,有的在8位引入第2个氟…     

抗HIV药物的体外筛选和研究方法

合适的体内外药物研究方法是研究和开发新药中最关键的环节之一，由于至今尚无理想的艾滋病（AIDS）动物模型，目前抗人免疫缺陷病毒（HIV）药物的筛选和研究仍然主要依赖于各种体外的筛选和研究方法。本文简要综述了抗HIV药物的体外筛选和研究方法。     

DNA编码化合物库技术新进展及其在生物医药领域的应用与展望

随着医药领域对靶向调节特定生命活动过程的新分子化合物的需求日益增加,高效、低成本地发现亲和配体分子的新型小分子药物筛选技术——DNA编码的化合物库(DNA encoded compound library,DEL)筛选技术应运而生。DEL作为组合化合物库,可以是简单小分子化合物的集合,也可以是具有高级空间结构的复杂小分子库,每个化合物都以共价方式与特异的DNA序列偶联,因而可将库中所有化合物与靶标蛋白进行合并筛选,随后使用高通量测序对DNA编码序列进行测序来鉴定结合的配体分子。近年来,应用DEL技术筛选开发候选药物的例子已越来越多地被报道,本文回顾和总结了DEL技术的实施流程,特别是DEL库构建和亲和筛选方法的最新研究进展,展示了利用DEL技术筛选开发的最新亲和配体分子,并对DEL技术在生命科学领域的应用前景作了展望。     

DNA编码化合物库技术用于药物筛选的策略进展

目的 综述DNA编码化合物库(DNA encoded compound library, DEL)技术用于药物筛选的策略进展。方法 检索国内外相关文献,根据筛选体系的不同对DEL筛选策略进行分类阐述。结果 DEL技术主要包括文库的构建、化合物的筛选和命中解码与重构化合物三个部分。其中,化合物的筛选技术作为DEL技术的中心环节已成为近年来的热门话题。为了扩增DEL技术应用的靶标范围,DEL筛选体系从最初的固相逐步发展成为液相,靶标体系从纯化蛋白逐步扩展到细胞裂解液和活细胞。近年来,DEL技术相继与多种现代技术联用,从基于亲和力的结合筛选转变到生化活性筛选,提高了筛选结果的准确性。结论 DEL筛选具有广阔的技术前景,研究者们正在为DEL筛选进行进一步的研究,预计未来能够继续取得更多实质性突破,用于更多药物的发现。     

高效液相色谱法测定人体地尔硫及其主要代谢物的药物动力学

用高效液相色谱法（ＨＰＬＣ）测定人血清中地尔硫（ＤＺ）及去乙酰地尔硫（Ｍ１）浓度。以ＳｐｈｅｒｉｓｏｒｂＯＤＳ，５μｍ为层析柱，流动相：甲醇∶乙腈∶水（６０∶１０∶３０），检测波长２３７ｎｍ，以盐酸普罗帕酮为内标。检测范围：ＤＺ为５．４５～２７２．５ｎｇ·ｍｌ－１，Ｍ１为５．８５～２９２．５ｎｇ·ｍｌ－１。最低检测浓度：ＤＺ为２．８７ｎｇ·ｍｌ－１，Ｍ１为１．９９ｎｇ·ｍｌ－１。平均回收率ＤＺ为１０１．８８％，Ｍ１为１０１．７２％，ＲＳＤ均在１２％以内。并对４名受试者口服９０ｍｇ盐酸地尔硫片后，其药时曲线经微机用ＰＫＢＰ－Ｎ１程序拟合，ＤＺ为一房室开放模型，Ｍ１为二房室开放模型，求得ＤＺ和Ｍ１的Ｔ１／２分别为５．６±１．５ｈ和１４±７ｈ。     

Proteomics as a tool in the pharmaceutical drug design process

Proteomics is a technology platform that is gaining widespread use in drug discovery and drug development programs. Defined as the protein complement of the genome, the proteome is a varied and dynamic repertoire of molecules that in many ways dictates the functional form that is taken by the genome. The importance of proteomics is a direct consequence of the central role that proteins play in establishing the biological phenotype of organisms in healthy and diseased states. Moreover, proteins constitute the vast majority of drug targets against which pharmaceutical drug design processes are initiated. By studying interrelationships between proteins that occur in health and disease and following drug treatment, proteomics contributes important insight that can be used to determine the pathophysiological basis for disease and to study the mechanistic basis for drug action and toxicity. Proteomics is also an effective means to identify biomarkers that have the potential to improve decision making surrounding drug efficacy and safety issues based on data derived from the study of key tissues and the discovery and appropriate utilization of biomarkers.     

Knowledge-based approaches in the design and selection of compound libraries for drug discovery

In the past decade, the pharmaceutical industry has realized the increasing significance of impacting the early phase hit-to-lead development in the drug discovery process. In particular, knowledge-based approaches emerged and evolved to address a multitude of issues such as absorption, distribution, metabolism and excretion (ADME), potency, toxicity and overall drugability. Each of these approaches seeks to bring together all relevant pieces of information and create a knowledge-oriented process to deploy such information in drug discovery. This review focuses on work relating to drugability, which aims at obtaining hits (or leads) that have enhanced likelihoods of leading to successful clinical candidates by medicinal chemistry efforts. The period covered in this review is from 1997 (since the publication of Lipinski's rule of 5) to March 2002.     

Silica xerogels as pharmaceutical drug carriers

This review focuses on silica xerogels obtained by the sol-gel method and their application as drug delivery systems. SiO₂ xerogels are potential biomaterials to be used as matrix materials for the extended and controlled release of different kinds of biologically active agents administered by various routes. The article includes some representative examples that describe the encapsulation of bioactive molecules and model compounds inside a silica matrix produced by the conventional sol-gel method or by ultrasound hydrolysis. The drug release rate from xerogels could be modified by adjusting several parameters, such as the type of precursor, the concentration of the catalyst and drying temperature. In vitro and in vivo studies have shown the efficacy and biodegradability of these composites. The potential application of silica xerogels as drug carrier systems is critically analyzed and discussed.     

Lipid microspheres as drug carriers: a pharmaceutical point of view

The lipid microsphere (LM) formulation (Lipo-PGE₁) of prostaglandin E₁ (PGE₁) is an excellent pharmaceutical with a high degree of clinical efficacy. This review describes, from the pharmaceutical point of view, an attempt to clarify the physicochemical properties of LM for injection. Almost all PGE₁ was retained in the LM particles in Lipo-PGE₁, and was present at the oil-water interface. The high retentivity of PGE₁ in the LM particles was clarified when the mixture of Lipo-PGE₁ and transfusion was used in the clinical treatments. The evaluation of emulsion stability is most important to formulate LM. We established a method to evaluate the emulsion stability by considering flocculation and coalescence separately. This method is useful for predicting the stability of LM.     

Cyclotides as a basis for drug design

Introduction: Cyclotides are plant-made defence proteins with a head-to-tail cyclic backbone combined with a conserved, six cystine knot. They have a range of biological activities, including uterotonic and anti-HIV activity, which have attracted attention to their potential pharmaceutical applications. Furthermore, their unique structures and high stability make them appealing as peptide-based templates for drug design applications. Methods have been developed for their production, including solid phase peptide synthesis as well as recombinant methods.

Areas covered: This article reviews the recent literature associated with therapeutic applications of naturally occurring and synthetically modified cyclotides. It includes applications of cyclotides and cyclotide-like molecules as peptide-based drug leads and diagnostic agents.

Expert opinion: The ultra-stable cyclotides are promising templates for drug development applications and are currently being assessed for the potential breadth of their applications. For synthetic versions of cyclotides to enter human clinical trials further studies to examine their biopharmaceutical properties and toxicities are required. However, several promising proof-of-concept studies have established that pharmaceutically relevant bioactive peptide sequences can be grafted into cyclotide frameworks and thereby stabilised, while maintaining biological activity. These studies include examples directed at cancer, cardiovascular disease and infectious diseases. Solid phase peptide synthesis has been the preferred approach for making pharmaceutically modified cyclotides so far, but promising progress is being made in biological approaches to cyclotide production.