bluuebunny/crossref_metadata_2025_split huggingface dataset:
Docking and Scoring in Drug Discovery
Authors: Spyrakis Francesca , Cozzini Pietro , Kellogg Glen Eugene 
Published: September 2010

AbstractThe 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.
Angiotensin‐Converting Enzyme Inhibitors
Authors: Petrillo Edward W. 
Published: September 2010

AbstractThe discovery of captopril, the first orally active angiotensin‐converting enzyme inhibitor, showed that blockade of the renin‐angiotensin system effectively lowers blood pressure in a wide spectrum of patients with hypertension. Captopril was designed using a hypothetical model of the enzyme active site that subsequently guided the design of new classes of inhibitors. Because ACE inhibitors retard the progression of cardiovascular disease and the complications of diabetes, leading to an overall reduction in mortality, they have become one of the most widely used drug classes in cardiovascular medicine. New genetic and structural evidence has revealed that ACE has two functional catalytic domains with differences that may be exploited in the future to design inhibitors with superior properties.
Anticoagulants
Authors: Henry Brian L. , Desai Umesh R. 
Published: September 2010

AbstractThrombotic disorders are a major cause of morbidity and mortality in humans. Examples of thrombotic disorders include pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, acute myocardial infarction, unstable angina, and cerebrovascular thrombosis. Anticoagulants are the mainstay of treatment and prevention of these disorders. The most widely used anticoagulants include unfractionated heparin, low molecular weight heparins and warfarin. Newer agents introduced in the past decade include bivalirudin, fondaparinux, and argatroban. Mechanistically, these anticoagulants either directly inhibit thrombin or indirectly reduce the activity of thrombin and factor Xa. Several new molecules have been recently designed to directly inhibit thrombin and factor Xa with high potency and considerable selectivity, of which dabigatran and rivaroxaban were approved for clinical use in few countries in 2008. Molecules being pursued in clinical trials include AZD0837, LB‐30870, otamixaban, apixaban, YM‐150, and others. Ximelagatran, which was introduced in 2004 as a direct thrombin inhibitor, was taken off the market within 20 months due to significant hepatotoxicity. Indirect anticoagulants utilize the antithrombin‐mediated conformational activation and bridging mechanisms for inhibiting coagulation enzymes. Among the indirect anticoagulants that are currently being investigated in clinical trials are a biotinylated idraparinux and SR123781. Over the last two decades, major conceptual strides have been made including the design of the first anticoagulant based solely on factor Xa inhibition (fondaparinux) and the establishment of the paradigm that anticoagulation is possible without frequent laboratory monitoring (ximelagatran). Current work attempts to establish other concepts such as the dual inhibition of free and clot‐bound thrombin by a heparin‐based molecule (ORG42675) and the applicability of neutral P1‐group containing active site‐directed molecules as effective inhibitors of coagulation enzymes (rivaroxaban). To date, no molecule has been designed that satisfies all the properties of an ideal anticoagulant including a broad therapeutic window, absence of bleeding risk, no requirement for frequent coagulation monitoring, oral bioavailability, availability of an effective antidote, lack of hepatoxicity and absence other adverse effects. Yet, the newer agents are likely to be more attractive than the heparin‐ and coumarin‐based therapy. In this chapter, we review the structure, design, and mechanism of action of clinically used and new potential anticoagulants. Special emphasis is placed on the molecular interaction of anticoagulants with their targets.
The Role of Translational Medicine and Predictive Biomarkers in the Development of Novel, Innovative Treatments for the Management of Chronic Heart Failure:APharmaceutical Industry Perspective
Authors: Douglas Stephen A. , Feuerstein Giora Z. 
Published: September 2010

AbstractChronic 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.
Nuclear Hormone Receptor Medicinal Chemistry
Authors: Cheng Peter T.W. , Kick Ellen , Mukherjee Ranjan 
Published: September 2010

AbstractThis chapter will be focused on recent advances in the medicinal chemistry of agonist, antagonist, and modulator ligands of selected nuclear hormone receptors (NHRs) that are of special interest in the metabolic diseases therapeutic area (diabetes, obesity and dyslipidemia/atherosclerosis). These NHRs include established biological targets such as the peroxisome proliferator‐activated receptors (PPARs), the liver X receptors (LXRs), and the farnesoid X receptors (FXRs), for which ligands have reached either clinical development or have been approved for clinical usage. Other more recent targets of interest to metabolic diseases include HNF and Rev‐erb.
Anti‐Inflammatory Glucocorticoids
Authors: Avery Mitchell A. , Chittiboyina Amar G. 
Published: September 2010

Abstract

Glucocorticoids are the first line medication used in the treatment of afflictions ranging from the moderate skin rash to severe acute inflammatory disorders. They exert their activity through binding to the glucocorticoid receptor, a ligand‐dependent transcription factor, and result in either activation or repression of a large set of glucocorticoid responsive genes. The
glucocorticoid receptor
(
GR
) is a cytoplasmic protein of complex structure that is associated with various heat shock proteins (e.g., hsp 90). The desired immunosuppressive effect is apparently due largely to the downregulation of a variety of proinflammatory factors, whereas adverse reactions such as corticoid‐induced diabetes and osteoporosis could be connected to the inappropriate activation of genes involved in the control of metabolic processes. The discovery of selective receptor modulators, which maintain beneficial therapeutic activity together with a diminished risk of side effects, focuses on ligands that lead to repression rather than activation of genes targeted by the glucocorticoid receptor. Current drug‐screening programs have yielded a number of molecules including steroidal as well as nonsteroidal compounds, which preferentially induce receptor‐mediated repression.
Diabetes Drugs: Present and Emerging
Authors: Tilley Jefferson , Grimsby Joseph , Erickson Shawn , Berthel Steven 
Published: September 2010

AbstractThis chapter includes a summary of the mechanism of action, history, and ADME properties compounds selected from four classes of marketed drugs for the treatment of type 2 diabetes. These include the biguanides (metformin), α‐glucosylase inhibitors, sulfonylureas, and glinides. In addition, a discussion of several advanced, emerging classes of drugs together with lead structures is provided. The mechanistic classes of emerging drugs include inhibitors of the sodium glucose cotransporter 2 (SGLT2), glucokinase activators (GKAs), inhibitors of fructose‐1,6‐bisphosphatase (FPase), inhibitors of 11‐β‐sterol dehydrogenase (11‐β‐HSD1), agonists acting on the G‐coupled‐protein receptor GPR119, and mimics of the sirtuin family member SIRT1.
Kinase Inhibitors: Approved Drugs and Clinical Candidates
Authors: Bradbury Robert H. 
Published: September 2010

AbstractDuring the past two decades, protein kinases involved in a wide range of cellular signaling pathways have proved a tractable class of oncology drug target, and by the end of 2008 nine small‐molecule kinase inhibitors had been approved by regulatory authorities for treatment of human hematological or solid tumors. The majority of protein kinase inhibitors that have progressed to clinical evaluation target the adenosine triphosphate binding site. After a brief overview of design of the pioneering Bcr‐Abl kinase inhibitor imatinib, this chapter is structured around the effect of kinase inhibitor drugs on the “hallmarks of cancer,” the acquired cellular capabilities that collectively promote malignant growth of solid tumors. The chapter continues by reviewing growth factor and antiangiogenic kinase inhibitors, approaches that have now been validated in large‐scale clinical trials, and then proceeds to discuss inhibitors implicated in the cell cycle, survival signaling, and tissue invasion and metastasis. Reviewed in the chapter are approximately 20 oncology kinase drug targets and 60 associated inhibitors with disclosed chemical structures that have been approved by regulatory authorities or are undergoing clinical trials. Synopses of evolution from lead to candidate drug distilled from original articles illustrate themes in kinase inhibitor medicinal chemistry.
CNSCancers
Authors: Graeme Robertson 
Published: September 2010

AbstractCNS tumors represent a diverse collection of tumor types driven by a range of signaling inputs that often generate highly aggressive and at the same time heterogeneous tumor types. The effect of these tumors is particularly dramatic and impacts on children as well as adults. Malignant CNS tumors are characterized by being highly heterogeneous, aggressive, and frequently invasive, leading to poor overall patient survival times. As CNS tumors present within the nervous system, there are particular challenges in the development of effective molecular‐targeted therapies in dealing not only with the aggressive nature of these tumors and their ability to evade treatment but also, particularly, with maintaining normal neuronal and brain functions. Compounding this is the need to deliver systemically small molecules or other agents such as vaccines and for immunotherapy approaches to confront the complexity of the relationship between the nervous system and the immune system.Research to find effective treatments for CNS tumors is being facilitated by two key inputs both of which are reviewed in this chapter; first, a much greater understanding of tumor pathobiology and the potential role of developmental signaling pathways and tumor stem‐like cells, and by the development of animal models that more adequately represent endpoints measurable in the clinic. Together, these advances should assist in the selection of better targets and the optimization of better compounds to progress into clinical trials.
Antimalarials
Authors: Smithson David C. , Armand Guiguemde W. , Kiplin Guy R. 
Published: September 2010

AbstractWhile the treatment of malaria has until recently relied upon a small number of therapeutic agents with a few mechanisms of action, the past decade has seen a huge growth in the number of targets being addressed and new agents being pushed to the clinic. This chapter briefly reviews existing agents and close homologs in development and then carefully explores new targets and new chemotypes being developed.
HIVReverse Transcriptase Inhibitors
Authors: De Clercq Erik 
Published: September 2010

AbstractThe first antiviral compound ever shown to be activein vitroagainst HIV (human immunodeficiency virus) (originally referred to as HTLV‐III (human lymphotropic virus type III) and LAV‐1 (lymphadenopathy‐associated virus type 1)) was suramin; suramin was also the first antiviral found to be effectivein vivoin the treatment of HIV infections. Suramin was explored as a potential strategy for the therapy of AIDS because it has been recognized as a potent inhibitor of the reverse transcriptase (RT) associated with a number of animal retroviruses. Later, it became evident that suramin primarily acts against HIV infections as an inhibitor of virus adsorption rather than an RT inhibitor.
Approaches to Amyloid Therapies for the Treatment of Alzheimer's Disease
Authors: Robichaud Albert J. , Kim Ji‐In , Jacobsen J. Steven 
Published: September 2010

AbstractRecognized 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.
Electrical Properties
Authors: Mathes Kenneth N. 
Published: September 2010

AbstractPolymers, both uncompounded and compounded, are used in many electrical applications, often as primary electrical insulation. In other cases, such plastics may have primarily a structural function, but also an electrical function. The electrical behavior of insulating materials is influenced by temperature, time,mositure, and other contaminants, geometric relationships, mechanical stress and electodes, and frequency and magnitude of the applied voltage. These factors interact in a complex fashion. These article covers theoretical aspects, electric breakdown, conductive resistance, alternating current characteristics, and special electrical characteristics. The electrical properties of plastics are measured to determine performance capability in electrical applications; evaluate characteristics other than electrical; provide quality assurance; to serve as a means of identification and research tool; and to provide a basis for the buyer‐seller relationship.
Self‐Healing Polymers
Authors: Wilson Gerald O. , Andersson H. Magnus , White Scott R. , Sottos Nancy R. , Moore Jeffrey S. , Braun Paul V. 
Published: September 2010

AbstractIncreasing demand for petroleum and the effect of the use of petroleum products on the environment continue to create the need for more sustainable technologies. Self‐healing technologies present an opportunity to quickly add a sustainable dimension to materials that are already being used in a wide variety of applications. The present work is a discourse that includes the classification of self‐healing and related technologies into autonomic and non‐autonomic approaches and further sub‐classification into the various types of self‐healing systems including one‐capsule, dual‐capsule, and microvascular. The varying chemistries that have been evaluated in the disparate classes of self‐healing systems are also discussed along with the compartmentalization of the reactants, self‐healing performance, and evaluation in relevant applications.
Olfaction
Authors: Wilson Donald A , Chapuis Julie , Wesson Daniel W 
Published: September 2010

Abstract

Olfaction, the ability to recognise and discriminate myriad airborne molecules with great accuracy and sensitivity, is one of the most remarkable but least understood senses. It permits continuous monitoring of the surroundings for small volatile molecules, including chemical signals that identify territories, food, predators and mates; thus, olfaction plays a key role in survival and adaptation. Recent work suggests that in mammals, odour perception begins through volatile molecules binding to a subset of several hundred G protein‐coupled receptors on the olfactory sensory neurons in the nose. The identity of the odorant is encoded by a spatiotemporal pattern of activity within the first central relay, the olfactory bulb. The olfactory cortex then functions as a combinatorial array that allows recognition of those odorant‐specific patterns, and forms synthetic odour percepts. This pattern recognition process is experience‐dependent, and thus odour discrimination and perception can be affected by a variety of memory and cognitive disorders.

Key Concepts:

Odorants are transduced by olfactory sensory neurons through a large family of G protein‐coupled receptors, with individual sensory neurons expressing a single type of receptor.

Olfactory sensory neurons project axons directly into the mammalian forebrain targeting the olfactory bulb, and are continually replaced throughout life.

Odorant identity is encoded by odour‐specific spatiotemporal patterns of activity in the olfactory bulb which emerge due to highly specific sensory neuron axonal projections.

In contrast to other sensory systems, the direct projection to the primary olfactory cortex does not pass through the thalamus, although there is an olfactory thalamocortical pathway.

Information about internal state, emotion, expectation and past experience can influence odour processing as early as the first central synapse, and odour learning can influence processing through the entire olfactory pathway.

Given that most natural odours are mixtures of many volatile components, odour perception is based on an experience‐dependent combinatorial process resulting in perception of synthetic odour objects.

Odour habituation is a central phenomenon involving changes in the strength of connections between specific neurons within the olfactory bulb and cortex.

Through extensive interaction with other sensory systems, olfaction plays a critical role in the perception of flavour and food.

Impairment in olfactory perception is a prevalent problem which is associated with a wide variety of neurological disorders.
Nicotinic Acetylcholine Receptors
Authors: Lindstrom Jon 
Published: September 2010

Abstract

Nicotinic acetylcholine receptors (AChRs) bind the neurotransmitter acetylcholine, triggering the opening of a cation channel. AChRs are part of a gene superfamily of transmitter gated ion channels that include receptors for glycine and γ‐amino butyric acid which have anion channels. Muscarinic AChRs are part of a gene superfamily of metabotropic G protein‐linked receptors. AChRs are formed from five homologous subunits arranged like barrel staves to form the channel. Subtypes of AChRs are defined by their subunit composition. Studies of AChR subunits in knockout and transgenic mice reveal much about the normal physiological roles of AChR subtypes and their roles in disease. AChRs are the targets of nicotine in addiction to tobacco, of auto‐antibodies and disease‐causing mutations. They are also the targets of drug development for treatment of addiction and diseases of mood, cognition and neurodegeneration.

Key Concepts:

Nicotinic AChRs are the archetype for a superfamily of receptors which includes receptors for GABA and glycine.

AChR are formed by five homologous subunits organised around a central cation channel.

AChR subtypes are defined by their subunit composition.

AChRs serve many roles in excitatory intercellular signalling: as pre‐, post‐ and extra‐synaptic neurotransmitter receptors and as autocrine AChRs in nonneuronal tissues.

Nicotine acting on AChRs causes addiction to tobacco.

AChRs are involved in several diseases and are the targets of drug development for treatment of addiction, alcoholism, depression, schizophrenia, Alzheimer and Parkinson diseases and others.

The effects of nicotine and agonist drugs are complex because they can act on many AChR subtypes causing activation, desensitisation and upregulation.

Antibody‐mediated autoimmune responses to α1
*
AChRs cause myasthenia gravis and to α3
*
AChRs cause autonomic neuropathy. These diseases are models for the pathological mechanisms of autoantibodies to other receptors.

Mutations in α1
*
AChRs cause congenital myasthenic syndromes, and mutations in α4β2
*
AChRs cause autosomal dominant nocturnal frontal lobe epilepsy.