Burger's Medicinal Chemistry and Drug Discovery最新文献_第10页

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

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

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

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

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

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

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

引用次数: 0

HIV Reverse Transcriptase Inhibitors HIV逆转录酶抑制剂

Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC236

E. Clercq

引用次数: 1

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

引用次数: 0

Anti‐DNA Virus Agents 抗DNA病毒试剂

Burger's Medicinal Chemistry and Drug Discovery Pub Date : 2010-09-15 DOI: 10.1002/0471266949.BMC237

A. Holý, E. Clercq

{"title":"Anti‐DNA Virus Agents","authors":"A. Holý, E. Clercq","doi":"10.1002/0471266949.BMC237","DOIUrl":"https://doi.org/10.1002/0471266949.BMC237","url":null,"abstract":"Anti-DNA virus agents that are inhibitory to the replication of DNA viruses have been reviewed by Tim Middleton and Rockway in Burger's Medicinal Chemistry, 6th ed., volume 5. Here we will address the various agents effective against these different viruses. For each of the (classes of) compound(s), we will, where applicable, specifically focus on (i) the antiviral compounds that are clinically available; (ii) the antiviral compounds that are under (pre)clinical development; (iii) the mechanism of action of the compounds; (iv) their structure–activity relationship (SAR); (v) resistance that may have arisen; (vi) recent clinical data obtained with the compounds while under development. Previous reviews on antiviral agents have been dealing with “looking back in 2009 at the dawning of antiviral therapy now 50 years ago: an historical perspective,” highlighting the discovery of acyclovir [9-(2-hydroxyethoxymethyl)guanine] as a specific antiherpetic agent, “the design of drugs for HIV and HCV,” “HIV drug development: the next 25 years,” “interferons at age 50: past, current, and future impact on biomedicine,” “the way forward in HCV treatment-finding the right path,” “antiviral treatment of chronic hepatitis B virus infections: the past, the present, and the future,” “antiviral agents active against influenza A viruses,” “the war against influenza: discovery and development of sialidase inhibitors,” “antivirals and antiviral strategies,” and “clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections.” \u0000 \u0000 \u0000Keywords: \u0000 \u0000antiviral compounds; \u0000cidofovir; \u0000DNA viruses; \u0000inhibitors; \u0000structure–activity relationship","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84237473","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: 2