Burger's Medicinal Chemistry and Drug Discovery最新文献

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Inhibitors of Kinesin Spindle Protein for the Treatment of Cancer 运动蛋白纺锤体蛋白抑制剂治疗癌症
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC217
G. Bergnes, M. Conlan, S. Knight
{"title":"Inhibitors of Kinesin Spindle Protein for the Treatment of Cancer","authors":"G. Bergnes, M. Conlan, S. Knight","doi":"10.1002/0471266949.BMC217","DOIUrl":"https://doi.org/10.1002/0471266949.BMC217","url":null,"abstract":"","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80419227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Atherosclerosis I: LDL Cholesterol Lowering 动脉粥样硬化I: LDL胆固醇降低
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC185
D. Burnett, H. Davis
{"title":"Atherosclerosis I: LDL Cholesterol Lowering","authors":"D. Burnett, H. Davis","doi":"10.1002/0471266949.BMC185","DOIUrl":"https://doi.org/10.1002/0471266949.BMC185","url":null,"abstract":"Lowering LDL cholesterol in patients has been directly linked to lowering the incidence of cardiovascular disease and represents one of the most successful avenues of medicinal chemistry. This chapter discusses current drugs on the market and in development that effectively lower this key biomarker of heart disease. Mechanistic pathways presented are HMG-CoA reductase inhibition, cholesterol absorption inhibition (NPC1L1 inhibition), and the use of bile acid sequestrants. New therapeutic targets, such as PCSK9, antisense apoB 100 and MTP inhibition, as well as combination therapy are also presented. \u0000 \u0000 \u0000Keywords: \u0000 \u0000bile acid sequestrants; \u0000ezetimibe; \u0000LDL cholesterol; \u0000lipid lowering agents; \u0000statins","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"1 1","pages":"303-330"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83205264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fundamentals of Steroid Chemistry and Biochemistry 类固醇化学和生物化学基础
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC053.PUB2
R. Brueggemeier, Pui-Kai Li
{"title":"Fundamentals of Steroid Chemistry and Biochemistry","authors":"R. Brueggemeier, Pui-Kai Li","doi":"10.1002/0471266949.BMC053.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC053.PUB2","url":null,"abstract":"Steroids are a unique class of chemical compounds found throughout the animal and plant kingdom. This class includes sterols such as cholesterol and ergosterol, bile acids, and steroid hormones. Chemical research on steroids began with isolation and structure determination, and major research efforts focused on total synthesis and on the development of numerous reactions for modifying the steroid scaffold. Methods in microbial transformations of steroids were developed to produce large quantities of steroid starting materials at reduced costs. Research in steroid biochemistry first began with studies on the biosynthesis and metabolism of steroids, followed soon thereafter by investigations on the biochemical mechanism of action of steroids. Over the past several decades, steroid biochemistry and molecular biology have focused on steroidogenic enzymes, nuclear steroid receptors, and gene expression. The discovery of the anti-inflammatory effects of cortisone in the treatment of rheumatoid arthritis and the report of the contraceptive effects of estrogen and progestin preparations illustrated for the first time that steroids could be considered as medicinal agents. As a result, extensive research on the medicinal chemistry, pharmacology, and clinical studies of steroid agonists and antagonists has evolved and continues to provide new insights and new medicinal agents for therapies in many different diseases and chemoprevention strategies. \u0000 \u0000 \u0000Keywords: \u0000 \u0000steroid synthesis; \u0000steroid biosynthesis; \u0000steroid metabolism; \u0000steroid receptors; \u0000cholesterol; \u0000pregnenolone; \u0000cortisol; \u0000aldosterone; \u0000progesterone; \u0000testosterone; \u0000estradiol","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"92 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91303756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 7
Drug Transport and Membrane Transport Proteins 药物转运和膜转运蛋白
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC027.PUB2
P. Swaan
{"title":"Drug Transport and Membrane Transport Proteins","authors":"P. Swaan","doi":"10.1002/0471266949.BMC027.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC027.PUB2","url":null,"abstract":"In order to exert their intended therapeutic goal, drugs need to cross epithelial barriers to reach their site of action. Transport proteins have critical physiological roles in nutrient absorption and transport of endogenous compounds. These systems can serve as useful pharmacological targets and may be utilized as a mechanism to increase drug absorption. However, there is little understanding of these proteins at the molecular level due to their resistance to crystallization. Numerous efforts have been made to characterize the P-glycoprotein efflux pump, the peptide transporter (PepT1), and the apical sodium dependent transporter (ASBT), which are important not only for their native transporter function but also as drug targets to increase absorption and bioactivity. In vitro and computational approaches have been applied to gain some insight into these transporters and their substrate specificities. This represents an opportunity for optimizing molecules as substrates for solute transporters and providing a further screening system for drug discovery. This chapter will demonstrates that future growth in knowledge of transporter function will be lead by integrated in vitro and in silico approaches. \u0000 \u0000 \u0000Keywords: \u0000 \u0000ASBT; \u0000bile acid; \u0000bioavailability; \u0000epithelia; \u0000MDR; \u0000multidrug resistance; \u0000Pep T1; \u0000peptide transport; \u0000P-glycoprotein; \u0000transport","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"2016 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86138341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
QM and QM/MM Approaches to Evaluating Binding Affinities 评估绑定亲和性的QM和QM/MM方法
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC143
K. E. Shaw, Christopher J. Woods, A. Mulholland
{"title":"QM and QM/MM Approaches to Evaluating Binding Affinities","authors":"K. E. Shaw, Christopher J. Woods, A. Mulholland","doi":"10.1002/0471266949.BMC143","DOIUrl":"https://doi.org/10.1002/0471266949.BMC143","url":null,"abstract":"Binding free energy predictions have the potential to play pivotal roles in the drug discovery process, ranging from aiding selection of hit molecules from large databases of compounds to optimizing lead structures. Calculation of relative binding free energies from molecular simulations (e.g., molecular dynamics or Monte Carlo simulations), though computationally intensive, have proved their worth in a number of pharmaceutical applications. Despite this, it is now clear that, in many cases, the methods typically used in such simulations to model molecular interactions have significant limitations. For example, in protein–ligand systems in which charge transfer or polarization are important, or where a metal ion is present in the binding site, conventional molecular mechanics (MM) methods may not represent binding accurately. Methods based on quantum mechanics (QM), for all or part of the system, are potentially more accurate. This chapter reviews recent advances in the growing field of calculating or predicting binding free energies using a quantum mechanical (i.e., quantum chemical, electronic structure) treatment of all or part of the system, for example, a QM description of the ligand alone (or with part of the binding site), coupled to a MM treatment of the protein (QM/MM calculations) or a QM description of the entire protein–ligand complex. \u0000 \u0000 \u0000Keywords: \u0000 \u0000drug design; \u0000free-energy calculations; \u0000protein–ligand simulation; \u0000quantum mechanics/molecular mechanics","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"66 1","pages":"725-752"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78730490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 4
Therapeutic Agents Acting on RNA Targets 作用于RNA靶点的治疗剂
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC025.PUB2
J. P. Rife
{"title":"Therapeutic Agents Acting on RNA Targets","authors":"J. P. Rife","doi":"10.1002/0471266949.BMC025.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC025.PUB2","url":null,"abstract":"There are many therapeutics that target RNA, such as streptomycin, gentamicin, and tetracycline; some of them have been in existence for many years. All of them bind to ribosomal RNA and alter normal ribosome function. The modern strategies of drug discovery and design pertain nearly exclusively to protein targets. However, the field of drug discovery for RNA targets is maturing rapidly, largely due to the exciting ribosome/drug complexes that have recently been solved. Potential RNA drug targets abound for bacterial, viral, and cellular systems. Nevertheless, questions remain as to whether or not compounds can be found that simultaneously satisfy RNA binding and pharmacological properties, such as absorption and membrane permeation. The range of interactions observed, from Coulombic to hydrophobic, and the predicted “drug-like” qualities of several ribosome binding antibiotics, suggest that the discovery of drugs that target RNA can be a general phenomenon. \u0000 \u0000 \u0000Keywords: \u0000 \u0000aminoglycosides; \u0000antibiotics; \u0000drug discovery; \u0000erythromycin; \u0000oxazolidinones; \u0000ribosome; \u0000tetracyclines","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"75 10 1","pages":"945-982"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83571547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Docking and Scoring in Drug Discovery 药物发现中的对接与评分
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC140
F. Spyrakis, P. Cozzini, G. Kellogg
{"title":"Docking and Scoring in Drug Discovery","authors":"F. Spyrakis, P. Cozzini, G. Kellogg","doi":"10.1002/0471266949.BMC140","DOIUrl":"https://doi.org/10.1002/0471266949.BMC140","url":null,"abstract":"The rational development of new lead compounds requires good understanding of the relationship between all the actors involved in a binding event (protein, ligand, water, metal ions, cofactors, etc.). Computational methods attempt to reproduce and predict the behavior of nature even though this can be very difficult. The docking/scoring paradigm is probably the most widespread and potentially useful computer-aided technique used in the discovery of new drugs. This paradigm can be analyzed as the sum of a “geometric” problem, that is, the implementation of algorithms to find the possible positions of a ligand in a receptor cavity, and a “chemistry” problem, that is, the evaluation of the solution list using good and realistic energy functions. In this chapter, we deal with the panorama of docking and scoring approaches and the related software packages. After a general introduction, some basic principles about the goodness and limits of experimental data used for computational simulations are described. Then an exhaustive examination of the most common docking methods and packages is carried out followed by an analysis of scoring functions developed to date, including the evolving consensus scoring approach. Next, several problems with the paradigm and their state-of-the-art partial solutions are discussed, including active site water, ionization states, tautomerization, flexibility, and the probability of more than one “correct” solution. Particular attention is paid for the upside and the downside of the problem in a short user guide for the docking and scoring beginner, followed by a conclusions and outlook. \u0000 \u0000 \u0000Keywords: \u0000 \u0000computational chemistry; \u0000free energy; \u0000ligand docking; \u0000modeling; \u0000scoring functions","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"63 1","pages":"601-684"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83868740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 11
Osteoporosis: Current and Future Anabolic Therapy 骨质疏松症:当前和未来的合成代谢治疗
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC205
J. Feyen, G. Rawadi
{"title":"Osteoporosis: Current and Future Anabolic Therapy","authors":"J. Feyen, G. Rawadi","doi":"10.1002/0471266949.BMC205","DOIUrl":"https://doi.org/10.1002/0471266949.BMC205","url":null,"abstract":"First page of article \u0000 \u0000 \u0000Keywords: \u0000 \u0000anabolic therapy; \u0000bone remodeling; \u0000osteoporosis; \u0000parathyroid hormone; \u0000selective androgen receptor modulator","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74666984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Role of Translational Medicine and Predictive Biomarkers in the Development of Novel, Innovative Treatments for the Management of Chronic Heart Failure: A Pharmaceutical Industry Perspective 转化医学和预测性生物标志物在慢性心力衰竭管理的新型创新治疗发展中的作用:制药行业的观点
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC187
S. Douglas, G. Feuerstein
{"title":"The Role of Translational Medicine and Predictive Biomarkers in the Development of Novel, Innovative Treatments for the Management of Chronic Heart Failure: A Pharmaceutical Industry Perspective","authors":"S. Douglas, G. Feuerstein","doi":"10.1002/0471266949.BMC187","DOIUrl":"https://doi.org/10.1002/0471266949.BMC187","url":null,"abstract":"Chronic heart failure (CHF) represents one of the few cardiovascular diseases with an incidence that continues to rise. While the socio-economic burden associated with this malignant disease remains high, recent attempts to develop novel, differentiated therapies for the management of CHF (ET-1, TNFα, dual ACE/NEP inhibitors) have met with failure due to lack of differentiated efficacy and/or safety concerns. Such disappointments have drawn attention to the difficulties faced today in (a) the selection of the most appropriate, innovative targets for the management of this disease; (b) the development of predictive biomarkers that validate the target, define compound pharmacodynamic/-kinetic (safety/efficacy) relationships, catalog disease modification, and/or assist in patient selection/stratification; and (c) optimal CHF clinical trial design. The present commentary discusses the role of Translational Medicine in the preclinical and clinical CHF Drug Discovery process and details how this emerging scientific discipline can be best used to minimize investment risk/cost. \u0000 \u0000 \u0000Keywords: \u0000 \u0000cardiac remodeling; \u0000endothelin-1; \u0000heart failure; \u0000LV dysfunction; \u0000noninvasive imaging; \u0000patient stratification; \u0000pharmacokinetics; \u0000predictive biomarkers; \u0000target engagement; \u0000target validation; \u0000Translational Medicine; \u0000urotensin-II","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76831276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Application of Recombinant DNA Technology in Medicinal Chemistry and Drug Discovery 重组DNA技术在药物化学和药物发现中的应用
Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC023.PUB2
S. Basu, A. Oyelere
{"title":"The Application of Recombinant DNA Technology in Medicinal Chemistry and Drug Discovery","authors":"S. Basu, A. Oyelere","doi":"10.1002/0471266949.BMC023.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC023.PUB2","url":null,"abstract":"Drug discovery is usually a long and arduous process. However, pharmaceutical industries are making a significant progress in simplifying certain aspects of drug discovery process, especially in the area of target discovery, validation, and lead-compounds discovery. Advances in recombinant DNA technology are intimately connected with the explosion of newly identified pharmaceutically important targets, and an understanding of how these targets function to regulate biological processes of interest. This is providing new and exciting opportunities for therapeutic intervention in diseases including those diseases that were thought to be untreatable a few years back. In this chapter we describe how each stage of drug discovery, from target identification to lead generation and even clinical trials, have benefited from the tools of recombinant DNA technology. \u0000 \u0000 \u0000Keywords: \u0000 \u0000medicinal chemistry; \u0000drug discovery; \u0000recombinant DNA technology; \u0000protein engineering; \u0000site-directed mutagenesis","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"18 1","pages":"535-568"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88003798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
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