Comparative analysis of different DNA-binding drugs for leishmaniasis cure: a pharmacoinformatics approach

Several experiments have been performed to test DNA-binding drugs to cure Leishmania infection. However, there are no details of pharmacoinformatics study. Herein, we have selected a good number of compounds from experimentally verified studies and performed a comparative analysis based on pharmacoinformatics techniques. In silico docking study was performed to observe the molecular level interactions of these known ligands with the DNA receptor by automated computational docking using Glide. A comparison between the calculated interaction energies and in silico ADME/T study was made. In agreement with drug likeness rules, our study suggests that seco-hydroxy-aza-CBI-TMI (compound 4b; GScore, -12.058) is a potential molecule for targeting the DNA to cure leishmaniasis.     

雷公藤的肝毒性研究及ADME/Tox评价思路

雷公藤Triptergium wil fordii为卫矛科植物,具有多种药理作用,作为一种传统常用中药,其临床应用广泛,疗效显著,但使用中引起的肝损伤报道频繁发生。作为一种有毒中药,雷公藤本身所含化学成分多而复杂,且化合物多存在同物异名现象。现就雷公藤所含成分进行总结,并从相关临床病例报道出发,对雷公藤所致肝损害的特点及其可能的作用机制进行综述,提出基于ADME/Tox评价中药肝毒性的研究新思路,在原有的病理表征等传统研究方法的基础上,开展更为细致的中药毒性物质基础的研究。     

The role of DMPK science in improving pharmaceutical research and development efficiency

The successful regulatory authority approval rate of drug candidates in the drug development pipeline is crucial for determining pharmaceutical research and development (R&D) efficiency. Regulatory authorities include the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceutical and Food Safety Bureau Japan (PFSB), among others. Optimal drug metabolism and pharmacokinetics (DMPK) properties influence the progression of a drug candidate from the preclinical to the clinical phase. In this review, we provide a comprehensive assessment of essential concepts, methods, improvements, and challenges in DMPK science and its significance in drug development. This information provides insights into the association of DMPK science with pharmaceutical R&D efficiency.     

Fragment-based QSAR strategies in drug design

Recently, fragment-based drug design has been established as a crucial strategy for hit identification and lead generation, which has strongly encouraged the development of approaches to specifically recognize and evaluate molecular fragments or structural scaffolds that preferentially interact with particular sites of important biological targets. In this context, fragment-based quantitative structure–activity relationship (FB-QSAR) has emerged as a versatile tool to explore the chemical and biological space of data sets of compounds. FB-QSAR approaches have evolved from a classical use in the generation of standard QSAR models into advanced drug design tools for database mining, pharmacokinetic property prediction and optimization of multiple parameters. This paper provides a brief perspective on the evolution and current status of FB-QSAR, highlighting new opportunities in drug design.     

基于整合药理学策略的元胡止痛方研究进展

中药方剂是中医临床治疗的主要形式和手段,探索中药方剂的化学物质实体与机体生命活动的交互规律,是中药研究的关键科学问题之一。目前,中药研究存在整体与局部脱节、宏观与微观脱节、体内过程与活性评价脱节,整合药理学的提出,为解决中药研究"碎片化"问题提供了一条切实可行的途径。近年来,该课题组采用整合药理学策略,对元胡止痛方进行了系统研究,建立了"化学指纹-代谢指纹-网络靶标"和"肠吸收-活性评价-数据挖掘"2个研究模式,从计算、体外和体内多个层次建立了该方剂的化学成分与生物活性之间的交互规律,为该方剂的质量控制、药效物质基础及其药理作用机制提供了依据,该文对相关研究进展进行综述。     

Dermatotoxicology: Historical perspective and advances

The fundamental principles underlying the study of dermatotoxicology were developed by Arnold Lehman and John Draize over a half century ago and remain applicable today. This discipline has proven indispensable for addressing the problems associated with skin exposure to chemicals. The 55th anniversary of Lehman's landmark publication on safety factors presents the opportunity to reflect upon the historical beginnings of dermatotoxicology and the role of regulatory policies on the development of this field over the years. The complexity and sheer volume of information that has been collected makes it difficult to comprehensively cover all aspects of this vast discipline. This overview will touch upon the general concepts of ADME, the various forms of contact dermatitis, and transdermal drug delivery systems. The traditional tests performed in animals and humans to identify allergic or irritant potential of chemicals, in addition to alternative methods such as QSAR modeling will be discussed. The subspecialties of infant and occupational dermatotoxicology, as well as dermatotoxicology of aged and ethnic skin, and skin of the vulva and vagina will also be noted.     

The role of the human ABCG2 multidrug transporter and its variants in cancer therapy and toxicology

The human multidrug resistance ABC transporters provide a protective function in our body against a large number of toxic compounds. These proteins, residing in the plasma membrane, perform an active, ATP-dependent extrusion of such xenobiotics. However, the same proteins are also used by the tumor cells to fight various anticancer agents. ABCG2 is an important member of the multidrug resistance proteins, an 'ABC half transporter', which functions as a homodimer in the cell membrane. In this review, we provide a basic overview of ABCG2 function in physiology and drug metabolism, but concentrate on the discussion of mutations and polymorphisms discovered in this protein. Interestingly, a single nucleotide mutation, changing amino acid 482 from arginine to threonine or glycine in ABCG2, results in a major increase in the catalytic activity and a wider drug recognition by this protein. Still, this mutation proved to be an in vitro artifact, produced only in heavily drug-selected cell lines. In contrast, at least two, but possibly more polymorphic variants of ABCG2 were found to be present in large human populations with different ethnic background. However, currently available experimental data regarding the cellular expression, localization and function of these ABCG2 variants are strongly contradictory. Since, the proteins produced by these variant alleles may differently modulate cancer treatment, general drug absorption and toxicity, may represent risk factors in fetal toxicity, or alter the differentiation of stem cells, their exact characterization is a major challenge in this field.     

Drug interactions evaluation: An integrated part of risk assessment of therapeutics

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industry and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a “Drug Development and Drug Interactions” website to provide up-to-date information regarding evaluation of drug interactions (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.