Burger's Medicinal Chemistry and Drug Discovery最新文献

{"title":"Protein Flexibility in In Silico Screening","authors":"H. Gohlke, Hannes Kopitz","doi":"10.1002/0471266949.BMC148","DOIUrl":"https://doi.org/10.1002/0471266949.BMC148","url":null,"abstract":"We summarize computational approaches in structure-based ligand design (SBLD) and in silico screening that address issues of protein flexibility and mobility. In particular, we consider how protein plasticity can be incorporated into docking strategies. As a first requirement, one needs to detect what can move and how. Moving protein parts can be identified from experimental information as well as established computational techniques such as molecular dynamics (MD) simulations, graph theoretical and geometry-based approaches, or harmonic analysis-based methods. Second, this knowledge needs to be transformed into a docking algorithm. A multitude of approaches considering protein mobility has been introduced recently, with motions modeled either implicitly or explicitly. In the latter case, one can further distinguish between modeling of side-chain-only motions and motions including backbone changes. In all cases, accuracy needs to be balanced against efficiency. Case studies for which the inclusion of protein plasticity was crucial to success are noted along these lines. This allows us to identify scope and limitations of the current approaches, as well as guidelines for further developments. \u0000 \u0000 \u0000Keywords: \u0000 \u0000conformational selection; \u0000conformational variability; \u0000flexible docking; \u0000flexibility; \u0000induced fit; \u0000mobility; \u0000plasticity; \u0000protein–ligand","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"79 1","pages":"867-887"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85479940","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}

{"title":"PET and SPECT in Drug Development","authors":"A. Welch, S. Pimlott","doi":"10.1002/0471266949.BMC254","DOIUrl":"https://doi.org/10.1002/0471266949.BMC254","url":null,"abstract":"Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are noninvasive molecular imaging techniques that can be used to provide functional information in the living human body. They use radiolabeled compounds that bind to specific sites on a biological target, known as radiotracers, enabling us to visualize and characterize specific aspects of a biological process. This chapter describes these techniques and how they can be utilized in the drug development process. \u0000 \u0000 \u0000Keywords: \u0000 \u0000drug development; \u0000imaging; \u0000PET; \u0000SPECT","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89726306","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}

{"title":"Non-amyloid Approaches To Alzheimer's Disease","authors":"L. Veng, M. Savage, J. Barrow, C. Zerbinatti","doi":"10.1002/0471266949.BMC253","DOIUrl":"https://doi.org/10.1002/0471266949.BMC253","url":null,"abstract":"Alzheimer's disease (AD) brain is defined by extracellular amyloid plaques and intracellular Tau aggregates that are believed to cause the neurodegeneration and devastating cognitive dysfunction of AD patients. AD therapies have focused primarily on intervening at brain amyloid levels; however, since both small molecule and immunotherapy approaches to reduce amyloid have yet to show cognitive improvement in AD patients, interest in new interventions that can provide additional benefits is on the rise. This review focuses on therapeutic approaches addressing metabolic risk factors and development of targets that reduce Tau pathology. \u0000 \u0000 \u0000Keywords: \u0000 \u0000cholesterol; \u0000insulin; \u0000kinase inhibitors; \u0000LXR; \u0000methylene blue; \u0000microtubules; \u0000neurofibrillary tangles; \u0000PPAR; \u0000statins","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"58 1","pages":"405-446"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76594530","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}

{"title":"SNPs: Single Nucleotide Polymorphisms and Pharmacogenomics: Individually Designed Drug Therapy","authors":"A. M. Zee, B. Puckett, S. Terra, Joseph C. Walker","doi":"10.1002/0471266949.BMC072.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC072.PUB2","url":null,"abstract":"Pharmacogenomics is a rapidly expanding field aimed at understanding interpatient variability in drug response through the exploration and investigation of the human genome. It is an incontrovertible fact that large interpatient variability exists in response to medications. Variation in response has existed as long as medications have been used for the prevention and treatment of disease. In many ways, the field of pharmacogenomics began serendipitously in the 1950s after seminal observations describing variability in response to medications. Examples included peripheral neuropathy from isoniazid among slow acetylator, prolonged apnea from succinylcholine caused by pseudocholinesterase deficiency, and severe hypotension from debrisoquine among cytochrome P450 (CYP) 2D6 poor metabolizers. For the next 40 years, pharmacogenetic studies focused almost exclusively on the etiologies of altered variability in pharmacokinetic responses to medications. As we entered the 1990s, pharmacogenomic studies began to include studies that examined pharmacodynamic variability in drug response. Now instead of examining only differences in drug metabolizing enzymes, scientists began to focus on genes that encode drug transporters, drug targets, and ion channels. The ultimate goal of pharmacogenomics is to be able to accurately predict, based on an individual’s genomic information, which medications will provide the greatest benefit with the least harm, thus transforming medicine into an era of personalized therapeutics. This chapter provides a review of pharmacogenomics and how single nucleotide polymorphisms may impact pharmacotherapy and drug discovery. The chapter further explores the abundant recent literature as well as provides insight into some of the issues, limitations, and ethical considerations of pharmacogenomics. \u0000 \u0000 \u0000Keywords: \u0000 \u0000pharmacogenomics; \u0000pharmacogenetics; \u0000single nucleotide polymorphisms; \u0000SNPs; \u0000individualized pharmacotherapy","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"26 1","pages":"181-204"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73023859","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}

{"title":"Cancer Drug Resistance: Targets and Therapies","authors":"Barbara Zdrazil, G. Ecker","doi":"10.1002/0471266949.BMC215","DOIUrl":"https://doi.org/10.1002/0471266949.BMC215","url":null,"abstract":"Hundred years ago, Paul Ehrlich, the founder of chemotherapy, received the Nobel Price for Physiology or Medicine for his landmark immunological insights. Ehrlich postulated the existence of specific receptors (either associated with cells or distributed in the blood stream),whichmaybe regarded as side chains that bind antigens (“side-chain theory of immunity, ” see timeline in Fig. 1) [1]. According to him, each type of receptors is attuned to one special group of drugs [2]. He declared “wir m€ ussen zielen lernen, chemisch zielen lernen” (“we have to learn how to target chemically”)—Ehrlich already suspected that the key for synthetic chemistry was to modify some starting material in various ways. After the discovery of the antisyphilitic activity of Salvarsan—an organic arsenic compound—in 1908 in Paul Ehrlich’s laboratory, lead optimization led to the improved derivative Neosalvarsan in 1912. Biological activity of a lead compound for the first time was optimized through systematic modifications. This was the real beginning of chemotherapy [3,4]. It took some time—until the end of the World War II—that chemotherapy was introduced in clinical practice for cancer treatment. Gilman and coworkers treated a patient with non-Hodgkin lymphoma with nitrogen mustard, a chemical warfare agent that accidentally had caused lymphoid and myeloid suppression in humans duringWorldWar II. The therapy initially caused a dramatic antitumor effect, but by the time the third treatmentwas given, the tumor no longer responded to the chemotherapeutic treatment [4,5]. Since these early days of cancer chemotherapy, the increased knowledge of the cancer genome and the development of new drug discovery technologies, such as quantitative structure–activity relationships (QSAR), highthroughput screening (HTS), nuclearmagnetic resonance (NMR), X-ray diffraction, and protein–ligand cocrystallography, have paved the way for targeted andmultitargeted cancer therapeutics. Nevertheless, classical (unspecific cytotoxic) as well as targeted chemotherapy are often faced with one major obstacle that limits its success: drug resistance (tolerance).","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"23 1","pages":"361-382"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81717256","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}

{"title":"Nanotechnology in Drug Delivery","authors":"I. Uchegbu, A. Schätzlein","doi":"10.1002/0471266949.BMC168","DOIUrl":"https://doi.org/10.1002/0471266949.BMC168","url":null,"abstract":"Nanotechnology involves manipulating matter at the nanoscale (<1000 nm); that is, manipulations at less than thousandth of a millimeter, and for drug delivery applications this typically takes the form of creating nanoparticles (5 ∼ 800 nm) that are then used to package drug molecules and genes. By packaging pharmacologically active compounds within nanoparticles, nanomedicines are created. It is possible to control drug biodistribution and achieve therapeutic benefit with these nanomedicines. This chapter outlines the various chemistries and nanomedicine preparation strategies that have been used to produce nanoparticles and highlights the drug delivery benefits that are achievable from these nanoscale arrangements. The chemical compounds used to construct these nanomedicines are as follows: low molecular weight self-assembling amphiphiles, self-assembling amphiphilic polymers, polymer–drug conjugates, water insoluble polymers/cross-linked polymers, dendrimers, and carbon nanotubes. Engineering of these particles has produced nanomedicines that target drugs and genes to tumors and improve the brain delivery of peptides and other molecules. These particles are also capable of promoting oral drug absorption and drug transport across other biological barriers such as the cornea and the skin. Only a few of these technologies are commercially available presently, such as liposomes (e.g., Doxil®), low molecular weight micelles (e.g., Fungizone®), and polymer–drug conjugates (Oncaspar®); but the therapeutic benefits being observed in both preclinical studies and early clinical testing suggest that more of these technologies will emerge into the patient arena in the future. \u0000 \u0000 \u0000Keywords: \u0000 \u0000carbon nanotubes; \u0000chitosan; \u0000dendrimers; \u0000drug delivery; \u0000gene therapy; \u0000liposomes; \u0000nanomedicine; \u0000nanoparticles; \u0000poly(lactide-co-glycolide)-block-(polyethylene oxide); \u0000polymer–drug conjugates","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"25 1","pages":"469-492"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86841686","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}

{"title":"Synthetic Antibacterial Agents","authors":"N. Anand, W. Remers","doi":"10.1002/0471266949.BMC086.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC086.PUB2","url":null,"abstract":"Synthetic antibacterial compounds are divided into topical and systemic agents. Topical agents are called disinfectants or antiseptics depending on how they are used. They show little selectivity between the microbes and the host. Nevertheless, they are indispensable in hospitals, public health, and the home. \u0000 \u0000 \u0000 \u0000The development of systemic antibacterial agents had a strong dye connection. Ehrlich's development of selective staining methods led him to propose that dyes may also have selective toxicity for microbes, and to coin the term chemotherapy. Domagk's discovery of antibacterial activity for the azo dye prontosil led to the first effective chemotherapeutic agent, sulfanilamide. This compound provided an excellent lead for structural modification and ushered in the modern era of chemotherapy and drug design. The discovery that sulfonamides act through folate inhibition resulted in the development of dihydrofolate reductase inhibitors such as trimethoprim. \u0000 \u0000 \u0000 \u0000The availability of synthetic antibacterials and antibiotics, which were discovered almost concurrently, provided major advances in control of bacterial infections; however, the rise in bacterial resistance prompted the search for newer classes of agents. This search provided fluoroquinolines and oxazolidones. \u0000 \u0000 \u0000 \u0000There are also synthetic antibacterials with niche needs, such as nitrofurans and methenamine, which are used for urinary tract infections. \u0000 \u0000 \u0000Keywords: \u0000 \u0000antibacterial drug; \u0000dihydrofolate reductase inhibitors; \u0000sulfanilamide; \u0000synthetic antibacterial compounds; \u0000systemic agents; \u0000topical agents","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"8 1","pages":"481-562"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85408761","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}

{"title":"Gene Therapy with Plasmid DNA","authors":"S. R. Bathula, Leaf Huang","doi":"10.1002/0471266949.BMC073.PUB2","DOIUrl":"https://doi.org/10.1002/0471266949.BMC073.PUB2","url":null,"abstract":"Gene therapy is a promising therapeutic modality for the treatment of inherited as well as acquired genetic disorders. It can be defined as the use of nucleic acid transfer, either RNA or DNA, to treat or prevent a disease. Although initially most research on gene therapy has focused on the development of viral-mediated approaches to deliver therapeutic genes to cells both ex vivo and in vivo, nonviral gene medicines have emerged as a potentially safe and effective gene therapy method for the treatment of a wide variety of acquired and inherited disorders. Compared to viral vectors, this delivery system has received great attention due to their several favorable properties, including low toxicity and immunogenicity, resistance to nuclease, and their efficiency is independent on size of the genetic cargo. One of the simplest approaches of delivery is direct gene transfer with naked plasmid DNA to the organs of interest. Plasmid DNAs (pDNAs), which carry recombinant genes of interest, are used for introducing genes to cells and organs. Various physical methods, for example, gene gun, electroporation, sonoporation, and laser irradiation increase the efficiency of the naked DNA incorporation. Synthetic gene delivery vectors such as cationic lipids and cationic polymers have the advantage of protecting the DNA against degradation by endogenous DNase in vivo, and can be targeted to a specific cellular site in some special cases. Varieties of lipid-based systems have been designed, mostly containing cationic lipids of different structures. Vectors containing polymers, either synthetic or natural, have also been developed. Although significant progress has been made, nonviral vectors are still limited in their efficiency and by some cytotoxicity inherited in the bacterial pDNA, which hosts the gene of interest. Understanding mechanisms and means to overcome the cellular barriers for the DNA delivery will undoubtedly promote further development of pDNA-mediated gene delivery. Great advancement has recently been made in the delivery of oligonucleotides, including siRNA, by nonviral vectors. This is because the nuclear membrane is not a delivery barrier for most of the oligonucleotides. \u0000 \u0000 \u0000Keywords: \u0000 \u0000gene therapy; \u0000lipoplex; \u0000lipopolyplex; \u0000nonviral gene delivery; \u0000polyplex","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80035519","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}

{"title":"Protein–Protein Interactions as Drug Discovery Targets","authors":"A. Dömling","doi":"10.1002/0471266949.BMC129","DOIUrl":"https://doi.org/10.1002/0471266949.BMC129","url":null,"abstract":"Protein–protein interactions (PPIs) recently have been recognized as a major class of drug targets. Many of the successful “classical” biotechnology protein drugs are agonists or antagonists of PPIs and there are established pathways for their development. However, small molecular weight compounds as antagonists of PPIs still pose a major problem to discovery due to the inherent physicochemical properties of their targets. Recently, several small molecular weight antagonists of PPIs advanced into clinical trials and thus comprise a proof-of-concept to this young area in medicinal chemistry. This chapter summarizes the area of small molecular weight antagonists of PPIs with a focus on recent success stories. After a short introduction into the structural biology of PPIs, recognized important PPI targets, discovery pathways of their inhibitors are discussed. The PPI p53-Mdm2 with potential applications in cancer is used as a case study to demonstrate to diversity of approaches leading to many different lead structures. In contrast, the discovery of IL-2/IL-2 rec. antagonists is discussed to highlight adaptive high affinity binding to hotspot regions. \u0000 \u0000 \u0000Keywords: \u0000 \u0000computational docking; \u0000drug discovery target; \u0000FBA; \u0000HTS; \u0000PPI; \u0000protein–protein interaction","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"201 1","pages":"335-366"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76978405","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}

{"title":"Approaches to Amyloid Therapies for the Treatment of Alzheimer's Disease","authors":"Albert J. Robichaud, Ji-In Kim, J. Steven Jacobsen","doi":"10.1002/0471266949.BMC249","DOIUrl":"https://doi.org/10.1002/0471266949.BMC249","url":null,"abstract":"Recognized as the most common of the neurodegenerative disorders, Alzheimer's disease (AD) affects greater than 18 million people worldwide and is predicted to become the largest socioeconomic burden of the twenty-first century. The underlying mechanism of Alzheimer's disease is as yet unknown, but the growing body of pathophysiologic evidence is beginning to point to two main causes, the formation of β-amyloid plaques and neurofibrillary tangles. This review will cover approaches to disease modification that are based on the amyloid hypothesis; that being, the prevention of the accumulation, aggregation, and deposition of β-amyloid peptide (Aβ) monomers, leading first to multiple oligomeric species and then to fibrils and ultimately senile plaques, is the center of focus for an approach to disease modification. There is a wealth of evidence to implicate this peptide and its subsequent aggregation in the etiology of the disease and approaches, both small molecule and biopharmaceutical, to prevent its accumulation have been the subject of much research. The vast majority of this research over the last decade has been, and continues to be, focused on these disease-modifying, antiamyloidogenic approaches to AD. It is this subject, and the various approaches, past and present to amelioration of AD through the various agents being explored, that will be the focus of this chapter. \u0000 \u0000 \u0000Keywords: \u0000 \u0000active immunization; \u0000Alzheimer's disease; \u0000amyloid hypothesis; \u0000amyloid precursor protein; \u0000disease modifying treatments; \u0000fibrillization inhibitors; \u0000neurodegeneration; \u0000passive immunization; \u0000secretase","PeriodicalId":9514,"journal":{"name":"Burger's Medicinal Chemistry and Drug Discovery","volume":"1 1","pages":"329-404"},"PeriodicalIF":0.0,"publicationDate":"2010-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82937302","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}