Internet Resources Related to Drug Action and Human Response: A Review

It has been demonstrated that numerous proteins interact with drugs or their metabolites. Knowledge of these proteins is necessary to understand the mechanisms of drug action and human response. Progress in modern genetics, molecular biology, biochemistry and pharmacology is generating a comprehensive mechanistic understanding of drug-target interaction on the molecular level. This is valuable for researchers and pharmaceutical companies in their efforts to improve the efficacy of existing drugs and to discover new ones. Most recently, the integration of a systems biology approach into drug discovery processes calls for more holistic knowledge and easily accessible resources of the proteins that are important in drug action and human response. We have reviewed many publicly accessible internet resources of these proteins, according to their roles in drug action and human response, such as therapeutic effect, adverse reaction, absorption, distribution, metabolism and excretion.     

Sulfur-containing peptides: Synthesis and application in the discovery of potential drug candidates

Peptides act as biological mediators and play a key role of various physiological activities. Sulfur-containing peptides are widely used in natural products and drug molecules due to their unique biological activity and chemical reactivity of sulfur. Disulfides, thioethers, and thioamides are the most common motifs of sulfur-containing peptides, and they have been extensively studied and developed for synthetic methodology as well as pharmaceutical applications. This review focuses on the illustration of these three motifs in natural products and drugs, as well as the recent advancements in the synthesis of the corresponding core scaffolds.     

Needs for new plant-derived pharmaceuticals in the post-genome era: an industrial view in drug research and development

Plant metabolites have been the successful source of drugs and provided considerable value not only to the pharmaceutical industry but also to human health problems. Although pharmaceutical companies significantly decreased their activities in natural product discovery during the past few decades, various multidisciplinary approaches have been made to create new opportunities for finding innovative plant derived pharmaceuticals in post-genome era. Strategies to integrate the knowledge on medicinal plants into rational drug screening, the unique biodiversity of plant metabolites into random drug screening, and the chemical diversity of plant metabolites into combinatorial chemistry have been reviewed with concrete examples. Innovative biotechnologies in plant cell and tissue cultures, and the latest achievements in metabolic engineering and genetic modification should significantly improve the production sustainability and efficiency of plant-derived pharmaceuticals.     

二甲基亚砜毒性研究

二甲基亚砜(Dimethyl sulfoxide DMSO)是一种含硫有机化合物,被誉为"万能溶剂",广泛用作溶剂和反应试剂。在医药工业中,DMSO可直接用作某些药物的原料及载体。DMSO本身有消炎止痛,利尿,镇静等作用,亦誉为"万灵药",常作为止痛药物的活性组分添加于药物之中。DMSO也是一种渗透性保护剂,能够降低细胞冰点,减少冰晶的形成,减轻自由基对细胞损害,改变生物膜对电解质、药物、毒物和代谢产物的通透性。DMSO作为组蛋白去乙酰化酶抑制剂(Histone Deacetylases-inhibitor HDACi)的一种,同样具有恢复组蛋白的乙酰化与去乙酰化平衡,抑制细胞程序性死亡,修复DNA双螺旋结构,抗放射性损伤,抗炎症反应及抗癌作用。鉴于其应用广泛,本文就其物理特性及毒性研究做一综述。     

Drug discovery for malaria: a very challenging and timely endeavor

The prevalence of resistance to known antimalarial drugs has resulted in the expansion of antimalarial drug discovery efforts. Academic and nonprofit institutions are partnering with the pharmaceutical industry to develop new antimalarial drugs. Several new antimalarial agents are undergoing clinical trials, mainly those resurrected from previous antimalarial drug discovery programs. Novel antimalarials are being advanced through the drug development process, of course, with the anticipated high failure rate typical of drug discovery. Many of these are summarized in this review. Mechanisms for funding antimalarial drug discovery and genomic information to aid drug target selection have never been better. It remains to be seen whether ongoing efforts will be sufficient for reducing malaria burden in the developing world.     

二甲基亚砜毒性研究

二甲基亚砜（Dimethyl sulfoxide DMSO）是一种含硫有机化合物,被誉为＂万能溶剂＂,广泛用作溶剂和反应试剂。在医药工业中,DMSO可直接用作某些药物的原料及载体。DMSO本身有消炎止痛,利尿,镇静等作用,亦誉为＂万灵药＂,常作为止痛药物的活性组分添加于药物之中。DMSO也是一种渗透性保护剂,能够降低细胞冰点,减少冰晶的形成,减轻自由基对细胞损害,改变生物膜对电解质、药物、毒物和代谢产物的通透性。DMSO作为组蛋白去乙酰化酶抑制剂（Histone Deacetylases-inhibitor HDACi）的一种,同样具有恢复组蛋白的乙酰化与去乙酰化平衡,抑制细胞程序性死亡,修复DNA双螺旋结构,抗放射性损伤,抗炎症反应及抗癌作用。鉴于其应用广泛,本文就其物理特性及毒性研究做一综述。     

Unlocking the potential of natural products in drug discovery

The natural product specialized metabolites produced by microbes and plants are the backbone of our current drugs. Despite their historical importance, few pharmaceutical companies currently emphasize their exploitation in new drug discovery and instead favour synthetic compounds as more tractable alternatives. Ironically, we are in a Golden Age of understanding of natural product biosynthesis, biochemistry and engineering. These advances have the potential to usher in a new era of natural product exploration and development taking full advantage of the unique and favourable properties of natural products compounds in drug discovery.     

制剂技术在提高BCS IV类药物生物利用度中的应用及此类药物体内外相关性研究现状

随着组合化学和高通量筛选在药物发现中的广泛应用，新候选药物不断涌现，其中不乏各种BCS IV类药物，而该类药物凸显的低溶解性/低渗透性极大地阻碍了其进一步的临床开发与应用。因此，如何有效提高该类药物生物利用度，已成为药剂学研究者长期以来广泛关注并致力于解决的课题。分类综述制剂技术在改善BCS IV类药物溶解性/渗透性方面的应用研究，并简介该类药物的体内外相关性研究进展。     

Impact of drug discovery on stem cell biology

Despite the rapid technical progress in pharmaceutical industry in the past decade, it is still a great challenge to find new drugs and the situation seems more and more serious. However, the history of pharmaceutical industry clearly indicated that the significance of drug discovery went far beyond providing new drugs. For instance, drugs or candidates could be used as selective probes to reveal novel cellular mechanisms, which is a fundamental tenet of chemical biology. More interestingly, accumulating evidence indicates that drugs and candidates can find important use in stem cell biology. Not only approved drugs but also undeveloped pharmacological agents could serve as efficient agents to regulate stem cell fate. Moreover, the target and activity knowledge accumulated during the drug discovery process will help select the stem cell fate modulators in a rational manner. As the progress in stem cell biology will bring positive influence to drug discovery, it can be expected that the current drug discovery efforts will finally bear great fruits in the future.     

A Mapping of Drug Space from the Viewpoint of Small Molecule Metabolism

Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the “effect space” comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism.     

Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I)

Worldwide research efforts have driven recent pharmaceutical successes, and consequently, the emerging role of Protein-Protein Interactions (PPIs) as drug targets has finally been widely embraced by the scientific community. Inhibitors of these Protein-Protein Interactions (2P2Is or i-PPIs) are likely to represent the next generation of highly innovative drugs that will reach the market over the next decade. This review describes up-to-date knowledge on this particular chemical space, with a specific emphasis on a subset of this ensemble. We also address current structural knowledge regarding both protein-protein and protein-inhibitor complexes, that is, the 2P2I database. Finally, ligand efficiency analyses permit us to relate potency to size and polarity and to discuss the need to co-develop nanoparticle drug delivery systems.     

Microbial biotransformation: a tool for drug designing

For centuries microbial biotransformation has proved to be an imperative tool in alleviating the production of various chemicals used in food, pharmaceutical, agrochemical and other industries. In the field of pharmaceutical research and development, biotransformation studies have been extensively applied to investigate the metabolism of compounds (leads, lead candidates, etc.) using animal models. The microbial biotransformation phenomenon is then commonly employed in comparing metabolic pathways of drugs and scaling up the metabolites of interest discovered in these animal models for further pharmacological and toxicological evaluation. Microorganisms can conveniently afford drugs difficult obtained via synthesis. The plethora of reported microbial biotransformations along with its added benefits has already invoked further research in bioconversion of novel and structurally complex drugs. This review alternatively discusses the prospect of microbial biotransformation studies as a significant element ameliorating drug discovery and design in terms of cost-effectiveness, environment protection and greater structural diversity as compared to animal models used to study metabolism. To explicate the microbial biotransformation paradigm in drug designing 3 main areas in this aspect have been analyzed: 1—lead expansion: obtaining pharmacologically improved metabolites from bioactive molecules; 2—biosynthesis of precursors/intermediates involved in the production of bioactive molecules; 3—resolution of racemic mixture to obtain enantiomers possessing different pharmacological profiles.     

Polypharmacology and supercomputer-based docking: opportunities and challenges

Polypharmacology, the ability of drugs to interact with multiple targets, is a fundamental concept of interest to the pharmaceutical industry in its efforts to solve the current issues of the rise in the cost of drug development and decline in productivity. Polypharmacology has the potential to greatly benefit drug repurposing, bringing existing pharmaceuticals on the market to treat different ailments quicker and more affordably than developing new drugs, and may also facilitate the development of new, potent pharmaceuticals with reduced negative off-target effects and adverse side effects. Present day computational power, when combined with applications such as supercomputer-based virtual high-throughput screening (docking) will enable these advances on a massive chemogenomic level, potentially transforming the pharmaceutical industry. However, while the potential of supercomputing-based drug discovery is unequivocal, the technical and fundamental challenges are considerable.     

Analytical methods for the quantitative determination of selective serotonin reuptake inhibitors for therapeutic drug monitoring purposes in patients

Five selective serotonin reuptake inhibitors (SSRIs) have been introduced recently: citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Although no therapeutic window has been defined for SSRIs, in contrast to tricyclic antidepressants, analytical methods for therapeutic drug monitoring of SSRIs are useful in several instances. SSRIs differ widely in their chemical structure and in their metabolism. The fact that some of them have N-demethylated metabolites, which are also SSRIs, requires that methods be available which allow therapeutic drug monitoring of the parent compounds and of these active metabolites. Most procedures are based on prepurification of the SSRIs by liquid-liquid extraction before they are submitted to separation by chromatographic procedures (high-performance liquid chromatography, gas chromatography, thin layer chromatography) and detection by various detectors (UV, fluorescence, electrochemical detector, nitrogen-phosphorus detector, mass spectrometry). This literature review shows that most methods allow quantitative determination of SSRIs in plasma, in the lower ng/ml range, and that they are, therefore, suitable for therapeutic drug monitoring purposes of this category of drugs.     

The regional drug information service: a factor in health care?

Most regional health authorities throughout the United Kingdom have established drug information units to provide health service staff with a wide range of information about drugs and drug use. The units, which are staffed by drug information pharmacists, provide their service mainly by answering inquiries, although some disseminate information more positively through lectures and bulletins.An analysis of inquiries received by regional information units during 1976 showed that most were submitted by hospital doctors or pharmacists; comparatively few were received from general practitioners. Topics of inquiry included adverse effects of drugs, source of supply and identification, current treatment, dosage, route, precautions, and pharmaceutical problems such as stability or formulation of drug preparations. A more detailed analysis of the inquiries received by the North-western Regional Drug Information Service at Manchester over three years showed that the number of inquiries gradually increased and that more were received from general practitioners after a programme of lectures had been introduced to tell them about the service. The North-western service also received more requests from hospital pharmacists than other units, though many originated from clinicians.The regional drug information units consulted widely with clinical and other specialists in answering questions, but about a quarter of all inquiries were pharmaceutical, relating to stability and incompatibility. A multidisciplinary approach therefore seems necessary to provide a comprehensive and advisory drug information service.     

Bioavailability of oral drugs and the methods for its improvement

Recent studies in nanotechnology resulted in the development of novel formulations with improved bioavailability. This is especially important for oral administered drugs as the most convenient formulations for administration to patients. The review considers processes occurring in the gastro-intestinal (GI) tract during oral administration of drugs. The increase of bioavailability of the drug may be achieved through designing novel formulations according to the specific drug properties. These include capsules that release pharmaceutical agents at various parts of the GI tract, floating systems that prolong the presence of the drug in stomach, maximally dispersed forms containing surface-active soluble polymers or micelles that carry poor-soluble drugs inside their non-polar core, agents that facilitate tight junction opening, such as caprate and chitosan, and lipid-based formulations. The own data show the stimulating influence of phospholipid nanoparticles on peroral absorption of the drug, indomethacin, in rats and on passage of transport marker and drugs through Caco-2 cell monolayer in vitro. The review summarizes current understanding of factors that influence the bioavailability of the oral drug formulations, currently used models for pharmacokinetic studies, and various approaches to developing novel pharmaceutical formulations that increase the bioavailability of the drugs.     

Structure-directed combinatorial library design

In recent years pharmaceutical companies have utilized structure-based drug design and combinatorial library design techniques to speed up their drug discovery efforts. Both approaches are routinely used in the lead discovery and lead optimization stages of the drug discovery process. Fragment-based drug design, a new power tool in the drug design toolbox, is also gaining acceptance across the pharmaceutical industry. This review will focus on the interplay between these three design techniques and recent developments in computational methodologies that enhance their integration. Examples of successful synergistic applications of these three techniques will be highlighted. Opinion regarding possible future directions of the field will be given.     

Endophytic fungi as novel sources of biopesticides: the Macaronesian Laurel forest,a case study

Endophytes fungi have been widely bioprospected to find new drugs and drug leads including antimicrobial agents and antifungals. However, an important role in host plant protection has been suggested for their presence and their metabolites. Therefore, nematicidal and insecticidal effects of their metabolites should be expected. In this review, the literature data available on insecicidal and nematicidal compounds identified from fungal endophytes are presented. Additionally we present a recent study on the endophytic biodiversity of a unique paleoflora, the Macaronesian laurel forest, in the light of their role in plant protection.     

长效缓释微球制剂生产技术的发展现状

长效缓释微球是将药物溶解或分散在高分子骨架材料中的微米级别的药物释放载体,这种新剂型可以显著降低给药频率,同时大分子材料的包裹可以提高药物的稳定性,降低药物的毒副作用,目前广泛应用在蛋白多肽等药物。已有一些用于治疗糖尿病、精神病、子宫内膜异位等疾病的长效缓释微球制剂被批准上市。然而,因为微球的制备工艺繁杂、质量控制困难,至今只在少数产品上应用,现在越来越多的口服难吸收的生物药物开始产品化,长效缓释微球在提高患者依从性方面备受瞩目。本综述对目前典型的微球制备技术做出分析和评判,以期对完善微球制备工艺有所帮助。