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Current opinion in drug discovery & development最新文献

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The potential for caspases in drug discovery. 半胱天冬酶在药物发现中的潜力。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Sarah H MacKenzie, Joshua L Schipper, A Clay Clark
{"title":"The potential for caspases in drug discovery.","authors":"Sarah H MacKenzie,&nbsp;Joshua L Schipper,&nbsp;A Clay Clark","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Caspases are a family of proteases that are involved in the execution of apoptosis and the inflammatory response. A plethora of diseases occur as a result of the dysregulation of apoptosis and inflammation, and caspases have been targeted as a therapeutic strategy to halt the progression of such diseases. Hundreds of peptide and peptidomimetic inhibitors have been designed and tested, but only a few have advanced to clinical trials because of poor drug-like properties and pharmacological constraints. Although much effort has been focused on inhibiting caspases, there are many diseases that result from a decrease in apoptosis, thus activating procaspases could also be a viable therapeutic strategy. To this end, recent efforts have focused on the design of procaspase-3 activators. This review highlights the current progress in the rational design of both specific and pan-caspase inhibitors, as well as procaspase-3 activators.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"568-76"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289102/pdf/nihms357589.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29282398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Current understanding and importance of histone phosphorylation in regulating chromatin biology. 目前对组蛋白磷酸化在调节染色质生物学中的重要性的认识。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Beatriz Pérez-Cadahía, Bojan Drobic, Protiti Khan, Chaitra C Shivashankar, James R Davie
{"title":"Current understanding and importance of histone phosphorylation in regulating chromatin biology.","authors":"Beatriz Pérez-Cadahía,&nbsp;Bojan Drobic,&nbsp;Protiti Khan,&nbsp;Chaitra C Shivashankar,&nbsp;James R Davie","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The core histones H2A, H2B, H3 and H4, undergo various post-translational modifications, such as acetylation, methylation and phosphorylation. Core histone phosphorylation has roles in several biological responses, including transcription, mitosis, DNA repair and apoptosis. Histone phosphorylation may disrupt chromatin structure and/or provide a 'code' for the recruitment or occlusion of non-histone chromosomal proteins to chromatin. Among the better-characterized histone phosphorylation events are the phosphorylation of H3 at Ser10 and Ser 28, and the phosphorylation of the H2A variant H2A.X at Ser139. Much remains to be learned about the function of the many other core histone phosphorylation events in chromatin. This review provides an overview of the biological roles of core histone phosphorylation in mammalian cells.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"613-22"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29281255","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
Network biology as a new approach to drug discovery. 网络生物学作为药物发现的新途径。
Current opinion in drug discovery & development Pub Date : 2010-09-01
John A Lowe, Phil Jones, David M Wilson
{"title":"Network biology as a new approach to drug discovery.","authors":"John A Lowe,&nbsp;Phil Jones,&nbsp;David M Wilson","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The decline in productivity of the pharmaceutical industry may stem, at least in part, from underestimating the complexity of human disease. While a disease-relevant gene or protein may initially seem to be an attractive drug target, appreciating its role in the network of pathways involved in a disease provides a better perspective for making this decision. In some cases, off-target effects or redundancy in the network can negate the potential efficacy of a new drug. Even a successful drug, such as imatinib (Gleevec), may be less selective than originally thought, resulting in important, and sometimes useful, consequences. Advances in the area of network biology provide an important perspective on the potential of a drug target, and are being applied to various diseases. The impact of these advances on the field of drug discovery is assessed.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"524-6"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29281910","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
Orthosteric- and allosteric-induced ligand-directed trafficking at GPCRs. 正构和变构诱导的配体介导的gpcr转运。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Gregory J Digby, P Jeffrey Conn, Craig W Lindsley
{"title":"Orthosteric- and allosteric-induced ligand-directed trafficking at GPCRs.","authors":"Gregory J Digby,&nbsp;P Jeffrey Conn,&nbsp;Craig W Lindsley","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Many orthosteric agonists differentially activate downstream effectors of GPCRs. Such defined induction of signaling has strongly supported the hypothesis termed 'ligand-directed trafficking of receptor signaling' (LDTRS). More recently, subtype-selective GPCR activators, such as allosteric agonists and positive allosteric modulators, have also exhibited the capacity to activate specific signaling pathways. Based on this finding, it may be possible to achieve ligand-specific receptor active states that optimize the biological responses specific to GPCRs. This review discusses recent studies in which both orthosteric and allosteric compounds have been demonstrated to induce LDTRS.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"587-94"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821179/pdf/nihms515842.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29282400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The role of tau kinases in Alzheimer's disease. tau激酶在阿尔茨海默病中的作用。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Philip J Dolan, Gail V W Johnson
{"title":"The role of tau kinases in Alzheimer's disease.","authors":"Philip J Dolan,&nbsp;Gail V W Johnson","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A principal feature of the progression of Alzheimer's disease (AD) is the appearance of aberrant phosphorylation of the microtubule-associated protein tau in the brains of affected individuals. Significant research efforts have been directed at identifying the kinases involved in this process, as well as developing pharmacological agents to inhibit these molecules. This review focuses on recent developments in both the physiological and pathological effects of tau phosphorylation, and the contribution of phosphorylation to tau toxicity and pathological progression in AD. The evolving concepts of the roles tau plays in cellular biology, and the mechanisms by which phosphorylation regulates tau function, is reshaping the framework for the development of therapeutics targeting tau to treat AD.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"595-603"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941661/pdf/nihms233700.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29281254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Conformational ensembles, signal transduction and residue hot spots: application to drug discovery. 构象集成，信号转导和残基热点:在药物发现中的应用。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Saliha Ece Acuner Ozbabacan, Attila Gursoy, Ozlem Keskin, Ruth Nussinov
{"title":"Conformational ensembles, signal transduction and residue hot spots: application to drug discovery.","authors":"Saliha Ece Acuner Ozbabacan,&nbsp;Attila Gursoy,&nbsp;Ozlem Keskin,&nbsp;Ruth Nussinov","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A key step in drug development is the identification of both a protein target and its topological cellular network location and interactions, with regard to information flow in disease-causing events and to medication effects. Information flow involves a cascade of binding or covalent modification processes, with each step being affected by those that occur previously. Proteins are flexible, and information flows via dynamic changes in the distribution of conformational protein ensembles; molecular recognition is mainly determined by these changes. Drug discovery often focuses on signaling proteins situated at the crossroads of cellular networks; such signaling proteins have multiple partners that bind through shared binding sites. This review highlights these shared binding sites, and describes research to suggest that partners binding at these sites could at least partly interact via different energetically dominant 'hot-spot' residues. The data also indicate that, despite dynamic changes in the distribution of the conformational ensembles, the hot-spot conformations are retained in their pre-organized states.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"527-37"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29282394","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
Mechanisms of distribution and targeting of neuronal ion channels. 神经元离子通道的分布和靶向机制。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Desiree A Thayer, Lily Y Jan
{"title":"Mechanisms of distribution and targeting of neuronal ion channels.","authors":"Desiree A Thayer,&nbsp;Lily Y Jan","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The discovery and development of pharmaceutical drugs targeting ion channels is important for treating a variety of medical conditions and diseases. Ion channels are expressed ubiquitously throughout the body, and are involved in many basic physiological processes. Neuronal ion channels are particularly appealing drug targets, and recent advances in screening ion channel function using optical-based and electrophysiological technologies have improved drug development in this field. Moreover, methods for the discovery of peptide-based neurotoxins and other natural products have proven useful in the pharmacological assessment of ion channel structure and function, while also contributing to the identification of lead molecules for drug development.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"559-67"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29282397","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
Small-molecule PARP modulators--current status and future therapeutic potential. 小分子PARP调节剂——现状和未来治疗潜力。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Thomas D Penning
{"title":"Small-molecule PARP modulators--current status and future therapeutic potential.","authors":"Thomas D Penning","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>PARP-1 inhibitors have emerged as a promising therapeutic class of compounds, and numerous PARP inhibitors, including iniparib (BiPar Sciences Inc/sanofi-aventis), olaparib (AstraZeneca plc), veliparib (Abbott Laboratories), PF-1367338 (Pfizer Inc), MK-4827 (Merck & Co Inc) and CEP-9722 (Cephalon Inc), have advanced into clinical trials. Several additional inhibitors are expected to enter clinical trials within the next year. Early investigations with PARP-1 inhibitors involved non-oncological indications, but development has since progressed to focus primarily on oncology, for use both as single chemotherapeutic agents in specific patient populations (eg, BRCA-deficient) and as combination therapies with various chemotherapeutics. This review focuses on new developments in lead clinical PARP inhibitors, recent disclosures of new inhibitors and the potential use of PARP-1 inhibitors in new disease settings.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"577-86"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29282399","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
Modulation of the vasopressin system for the treatment of CNS diseases. 抗利尿激素系统在中枢神经系统疾病治疗中的调节作用。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Thomas Ryckmans
{"title":"Modulation of the vasopressin system for the treatment of CNS diseases.","authors":"Thomas Ryckmans","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Vasopressin (also known as arginine vasopressin [AVP]) is a small cyclic peptide that acts at the V1a, V1b and V2 GPCRs to regulate a wide range of physiological functions, including vasoconstriction, smooth muscle contractility, response to stress, and excretion of water and sodium via the kidney. The potential therapeutic applications of AVP receptor ligands have prompted significant interest in this target within the pharmaceutical research community, and several small-molecule drugs targeting the AVP receptor have reached the market, mainly for cardiovascular indications. The development of AVP receptor modulators for the treatment of CNS indications has proven more challenging, and is the focus of this review. The regulatory role of AVP on the hypothalamic-pituitary-adrenal (HPA) axis suggests potential uses for AVP receptor modulators in various CNS indications, including depression, anxiety and post-traumatic stress disorder. Several clinical trials of V1a and V1b receptor antagonists in CNS indications have been conducted, but none of these drugs have reached the market. In recent years, the discovery of the key role of AVP in modulating complex social behaviors has provided a unique opportunity to understand the physiological mechanisms of social interactions. Ultimately, the ongoing research in this field may enable the development of treatments to alleviate the social deficits associated with conditions such as autism and schizophrenia. Given the large unmet medical need in these areas, a renewed interest in the field of CNS-penetrant AVP receptors modulators is expected.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"538-47"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29282395","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 the mTOR pathway in regulating food intake. mTOR通路在调节食物摄入中的作用。
Current opinion in drug discovery & development Pub Date : 2010-09-01
Brian M Wiczer, George Thomas
{"title":"The role of the mTOR pathway in regulating food intake.","authors":"Brian M Wiczer,&nbsp;George Thomas","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>mTOR is a principal effector of nutrient action, integrating nutritional inputs from glucose, amino acids and fatty acids, as well as growth factor and hormonal signals. The mTOR signaling pathway plays a vital role in regulating cell growth and proliferation, and has been studied extensively in a variety of metabolic and cancer models. However, only recently has the mTOR signaling pathway become implicated in the regulation of food intake. This review focuses on recent studies describing the role of hypothalamic and gastric mTOR signaling in suppressing food intake, and discusses the potential mechanisms through which this regulation occurs.</p>","PeriodicalId":10809,"journal":{"name":"Current opinion in drug discovery & development","volume":"13 5","pages":"604-12"},"PeriodicalIF":0.0,"publicationDate":"2010-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29281253","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
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