共查询到20条相似文献,搜索用时 31 毫秒
1.
Roderick E. Hubbard 《Neuropharmacology》2011,60(1):7-23
Structure-based methods are having an increasing role and impact in drug discovery. The crystal structures of an increasing number of therapeutic targets are becoming available. These structures can transform our understanding of how these proteins perform their biological function and often provide insights into the molecular basis of disease. In addition, the structures can help the discovery process. Methods such as virtual screening and experimental fragment screening can provide starting hit compounds for a discovery project. Crystal structures of compounds bound to the protein can direct or guide the medicinal chemistry optimisation to improve drug-like properties - not only providing ideas on how to improve binding affinity or selectivity, but also showing where the compound can be modified in attempting to modulate physico-chemical properties and biological efficacy. The majority of drug discovery projects against globular protein targets now use these methods at some stage.This review provides a summary of the range of structure-based drug discovery methods that are in use and surveys the suitability of the methods for targets currently identified for CNS drugs. Until recently, structure-based discovery was difficult or unknown for these targets. The recent determination of the structures of a number of GPCR proteins, together with the steady increase in structures for other membrane proteins, is opening up the possibility for these structure-based methods to find increased use in drug discovery for CNS diseases and conditions. 相似文献
2.
Haystead TA 《Current topics in medicinal chemistry》2006,6(11):1117-1127
Much attention has focused on the development of protein kinases as drug targets to treat a variety of human diseases including diabetes, cancer, hypertension and arthritis. To date, Gleevec is one example of a drug targeting protein that has successfully treated human cancer. Several other protein kinase inhibitors are in clinical development. However, protein kinases are in fact part of a larger collection of some 2000 distinct proteins expressed by the genome that like the protein kinases also bind purines (the purinome), either to be utilized as substrates or as co-factors in the form of NAD, NADP and co-enzyme A. The solution structures of many representative gene family members within the purinome show these proteins bind purines in a similar orientations to that observed in all protein kinases. Several non-protein kinase purine utilizing proteins are established drug targets such as HMG CoA reductase, dihydrofolate reductase, phosphodiesterase and HSP90. Searches of OMIM identifies many purine utilizing enzymes that are associated with inborn errors in metabolism. Inhibition of any one of which by a drug could lead to an undesirable side effect. The purinome is therefore somewhat of a drug discovery mixed blessing. It is a rich source of therapeutic targets, but also contains a large collection of diverse proteins whose inhibition could result in an adverse outcome. Drug discovery within the purinome should therefore encompass strategies that enable broad assessment of selectivity across the entire purinome at the earliest stages of the discovery process. In this article we review the purinome within the context of drug discovery and discuss approaches for avoiding off target binding during the discovery/lead optimization process with particular emphasis on use of proteome mining technology. 相似文献
3.
Han LY Zheng CJ Xie B Jia J Ma XH Zhu F Lin HH Chen X Chen YZ 《Drug discovery today》2007,12(7-8):304-313
Identification and validation of viable targets is an important first step in drug discovery and new methods, and integrated approaches are continuously explored to improve the discovery rate and exploration of new drug targets. An in silico machine learning method, support vector machines, has been explored as a new method for predicting druggable proteins from amino acid sequence independent of sequence similarity, thereby facilitating the prediction of druggable proteins that exhibit no or low homology to known targets. 相似文献
4.
Many drugs act on receptors coupled to heterotrimeric G proteins. Historically, drug discovery has focused on agents that bind to the receptors and either stimulate or inhibit the receptor-initiated signal. This is an approach that is both direct and logical, and has proven extremely fruitful in the past. However, as our understanding of G-protein signaling has increased, novel opportunities for drug development have emerged. RGS proteins are multifunctional GTPase-accelerating proteins that inactivate G-protein signaling pathways. GTPase-accelerating protein activity is a general feature of RGS proteins, and serves to facilitate the inactivation of the G protein rather than the receptor. Thus, agents that bind and inhibit RGS proteins could modulate endogenous neurotransmitter and hormone signaling, in a manner analogous to neurotransmitter uptake inhibitors. Here we discuss the potential of RGS proteins as drug targets. 相似文献
5.
Schmid MB 《Expert opinion on therapeutic targets》2001,5(4):465-475
Genomics has changed our view of the biological world in the past decade, providing both new information and new tools to characterise biological systems. Over 100 microbial genomes - including many of substantial clinical importance - have been fully or partially sequenced, pushing the search for novel antimicrobial compounds into the post-genomic era. Genomic information and associated new technologies have the potential to revolutionise the drug discovery process. Genomic methods have created a wealth of potential new antimicrobial targets; strategies are evolving to provide validation for these targets before chemical inhibitors are identified. The ability to obtain large amounts of purified target proteins and advances in X-ray crystallography have caused significant increases in available protein structures, which may foreshadow an increased effort in structure-based drug design. The post-genomics strategies used in antimicrobial drug discovery may have application for small molecule drug discovery in numerous therapeutic areas. 相似文献
6.
Knapp M Bellamacina C Murray JM Bussiere DE 《Current topics in medicinal chemistry》2006,6(11):1129-1159
Purine-binding proteins are of critical importance to all living organisms. Approximately 13% of the human genome is devoted to coding for purine-binding proteins. Given their importance, purine-binding proteins are attractive targets for chemotherapeutic intervention against a variety of disease states, particularly cancer. Modern computational and biophysical techniques, combined together in a structure-based drug design approach, aid immensely in the discovery of inhibitors of these targets. This review covers the process of modern structure-based drug design and gives examples of its use in discovery and development of drugs that target purine-binding proteins. The targets reviewed are human purine nucleoside phosphorylase, human epidermal growth factor receptor kinase, and human kinesin spindle protein. 相似文献
7.
《Expert opinion on therapeutic targets》2013,17(4):465-475
Genomics has changed our view of the biological world in the past decade, providing both new information and new tools to characterise biological systems. Over 100 microbial genomes – including many of substantial clinical importance – have been fully or partially sequenced, pushing the search for novel antimicrobial compounds into the post-genomic era. Genomic information and associated new technologies have the potential to revolutionise the drug discovery process. Genomic methods have created a wealth of potential new antimicrobial targets; strategies are evolving to provide validation for these targets before chemical inhibitors are identified. The ability to obtain large amounts of purified target proteins and advances in X-ray crystallography have caused significant increases in available protein structures, which may foreshadow an increased effort in structure-based drug design. The post-genomics strategies used in antimicrobial drug discovery may have application for small molecule drug discovery in numerous therapeutic areas. 相似文献
8.
Berger AB Vitorino PM Bogyo M 《American journal of pharmacogenomics : genomics-related research in drug development and clinical practice》2004,4(6):371-381
The genomic revolution has created a wealth of information regarding the fundamental genetic code that defines the inner workings of a cell. However, it has become clear that analyzing genome sequences alone will not lead to new therapies to fight human disease. Rather, an understanding of protein function within the context of complex cellular networks will be required to facilitate the discovery of novel drug targets and, subsequently, new therapies directed against them. The past ten years has seen a dramatic increase in technologies that allow large-scale, systems-based methods for analysis of global biological processes and disease states. In the field of proteomics, several well-established methods persist as a means to resolve and analyze complex mixtures of proteins derived from cells and tissues. However, the resolving power of these methods is often challenged by the diverse and dynamic nature of the proteome. The field of activity-based proteomics, or chemical proteomics, has been established in an attempt to focus proteomic efforts on subsets of physiologically important protein targets. This new approach to proteomics is centered around the use of small molecules termed activity-based probes (ABPs) as a means to tag, enrich, and isolate, distinct sets of proteins based on their enzymatic activity. Chemical probes can be 'tuned' to react with defined enzymatic targets through the use of chemically reactive warhead groups, fused to selective binding elements that control their overall specificity. As a result, ABPs function as highly specific, mechanism-based reagents that provide a direct readout of enzymatic activity within complex proteomes. Modification of protein targets by an ABP facilitates their purification and isolation, thereby eliminating many of the confounding issues of dynamic range in protein abundance. In this review, we outline recent advances in the field of chemical proteomics. Specifically, we highlight how this technology can be applied to advance the fields of biomarker discovery, in vivo imaging, and small molecule screening and drug target discovery. 相似文献
9.
Proteomics as a tool in the pharmaceutical drug design process 总被引:4,自引:0,他引:4
Proteomics is a technology platform that is gaining widespread use in drug discovery and drug development programs. Defined as the protein complement of the genome, the proteome is a varied and dynamic repertoire of molecules that in many ways dictates the functional form that is taken by the genome. The importance of proteomics is a direct consequence of the central role that proteins play in establishing the biological phenotype of organisms in healthy and diseased states. Moreover, proteins constitute the vast majority of drug targets against which pharmaceutical drug design processes are initiated. By studying interrelationships between proteins that occur in health and disease and following drug treatment, proteomics contributes important insight that can be used to determine the pathophysiological basis for disease and to study the mechanistic basis for drug action and toxicity. Proteomics is also an effective means to identify biomarkers that have the potential to improve decision making surrounding drug efficacy and safety issues based on data derived from the study of key tissues and the discovery and appropriate utilization of biomarkers. 相似文献
10.
Lapan KA Chapple JP Galcheva-Gargova Z Yang M Tao J 《Expert opinion on therapeutic targets》2002,6(4):507-516
There is an urgent need to develop novel classes of antibiotics to counter the inexorable rise of resistant bacterial pathogens. Modern antibacterial drug discovery is focused on the identification and validation of novel protein targets that may have a suitable therapeutic index. In combination with assays for function, the advent of microbial genomics has been invaluable in identifying novel antibacterial drug targets. The major challenge in this field is the implementation of methods that validate protein targets leading to the discovery of new chemical entities. Ligand-directed drug discovery has the distinct advantage of having a concurrent analysis of both the importance of a target in the disease process and its amenability to functional modulation by small molecules. VITA is a process that enables a target-based paradigm by using peptide ligands for direct in vitro and in vivo validation of antibacterial targets and the implementation of high-throughput assays to identify novel inhibitory molecules. This process can establish sufficient levels of confidence indicating that the target is relevant to the disease process and inhibition of the target will lead to effective disease treatment. 相似文献
11.
12.
Dormán G Puskás LG Fehér LZ Hackler L Lorincz Z Lang C Urge L Darvas F 《Acta pharmaceutica Hungarica》2006,76(1):3-9
The simultaneous identification of disease-specific protein targets and their small molecule binding partners, suitable as drug candidates, could radically reduce the timeline and costs of drug discovery and development. Comparative chemical proteomics provides a novel approach to achieve this goal through rapid detection of overexpressed proteins in diseased samples by the application of small molecule microarrays. The interacting small molecules enables direct affinity-based isolation and identification of the proteins. In the present paper we report comparative chemical proteomics studies on melanocytes and melanoma cell-lines, which led to the identification of 3 overexpressed proteins (e.g. -tubulin) together with their small molecule binding partner. 相似文献
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14.
Structural biology is an invaluable tool in modern drug discovery, providing key insights into the interactions of small-molecule drugs with their protein targets. As in many aspects of the drug discovery process, significant synergies can be realized in structural biology by the contemporaneous pursuit of many target proteins from a single structural and functional class. We will review some of those synergies here using the example of the protein kinases--an important class of drug targets that has recently been the subject of intensive study. We conclude by discussing some of the technical advances in X-ray crystallography that have enabled implementation of high-throughput structural biology as applied to drug lead optimization. 相似文献
15.
Src homology 2 (SH2) domains are found in many intercellular signal-transduction proteins which bind phosphotyrosine containing polypeptide sequences with high affinity and specificity and are considered potential targets for drug discovery. The protein p56lck is a member of the family of Src tyrosine kinase. The SH2 domain is thought to be responsible for the recruitment and regulation of p56lck kinase activity. There have been enormous efforts in the development of SH2 domain inhibitors for diseases such as cancer, osteoporosis and other diseases. This review focuses on current understanding of SH2 domain structure, mechanism and drug discovery with an emphasis on p56lck SH2 domain. A potential impact of the accumulated crystallographic effort on the development of methods for structure-based drug design is briefly addressed. 相似文献
16.
Ma'ayan A Jenkins SL Goldfarb J Iyengar R 《The Mount Sinai journal of medicine, New York》2007,74(1):27-32
The global relationship between drugs that are approved for therapeutic use and the human genome is not known. We employed graph-theory methods to analyze the Federal Food and Drug Administration (FDA) approved drugs and their known molecular targets. We used the FDA Approved Drug Products with Therapeutic Equivalence Evaluations 26(th) Edition Electronic Orange Book (EOB) to identify all FDA approved drugs and their active ingredients. We then connected the list of active ingredients extracted from the EOB to those known human protein targets included in the DrugBank database and constructed a bipartite network. We computed network statistics and conducted Gene Ontology analysis on the drug targets and drug categories. We find that drug to drug-target relationship in the bipartite network is scale-free. Several classes of proteins in the human genome appear to be better targets for drugs since they appear to be selectively enriched as drug targets for the currently FDA approved drugs. These initial observations allow for development of an integrated research methodology to identify general principles of the drug discovery process. 相似文献
17.
It has long been recognized that knowledge of the 3D structures of proteins has the potential to accelerate drug discovery, but recent developments in genome sequencing, robotics and bioinformatics have radically transformed the opportunities. Many new protein targets have been identified from genome analyses and studied by X-ray analysis or NMR spectroscopy. Structural biology has been instrumental in directing not only lead optimization and target identification, where it has well-established roles, but also lead discovery, now that high-throughput methods of structure determination can provide powerful approaches to screening. 相似文献
18.
多次跨膜蛋白作为连接细胞膜内外环境的重要渠道,参与多种信号的传导,调控细胞对外界刺激的响应。许多人类疾病都与多次跨膜蛋白功能异常密切相关,使它们成为理想的药物作用靶点。相较于以小分子和多肽为主导的现有治疗方式,基于抗体的药物具有特异性强等优势,为调控多次跨膜蛋白的功能提供了新的路径。然而,针对多次跨膜蛋白进行抗体药物研发也面临诸多挑战,其结构的复杂性产生了例如表位可及性、蛋白表达困难和蛋白动态构象等独特障碍,需要创新性策略来推动相应的抗体药物研发。对多次跨膜蛋白因复杂结构为抗体药物开发所带来的挑战进行探讨,以及对近年来为克服这些障碍所发展的新方法进行介绍,并且系统性总结目前在研的针对多次跨膜蛋白的抗体类药物。相信随着该领域的发展,从靶向多次跨膜蛋白的抗体药物研究中获得的见解不仅对改进治疗干预措施,而且对推进更广泛的药物研究创新具 相似文献
19.
Drugs exert their therapeutic effect by binding and regulating the activity of a particular protein or nucleic acid target. A large number of targets have been explored for drug discovery. Continuous effort has been directed at the search for new targets and more-extensive exploration of existing targets. Knowledge of these targets facilitates the understanding of molecular mechanisms of drugs and the effort required for drug discovery and target searches. Areas of progress, current focuses of research and development and the difficulties in target exploration are reviewed. The characteristics of the currently explored targets and their correlation to the level of difficulty for target exploration are analyzed. From these characteristics, simple rules can be derived for estimating the difficulty level of target exploration. The feasibility of predicting druggable proteins by using simple rules and sequence-derived physicochemical properties is also discussed. 相似文献