bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peptidomimetics for Drug Design
Authors: Estiarte M. Angels , Rich Daniel H. 
Published: November 2003

AbstractThe past and present role of peptidomimetics to drug discovery and protein design is summarized. The historical evolution of this area of research and the current state‐of‐the‐art research strategies are described. A detailed description of each of the peptidomimetics types that have appeared in the literature so far is discussed. Some examples are used to illustrate the drug design process that proceeds from the native peptide to a completely non‐peptide peptidomimetic structure. Special attention is given to important pharmaceutical targets such as the cysteine, metallo, serineor aspartic proteases, integrins, G‐protein–coupled receptors, etc. The principles currently used are highlighted in the discussions of some of the most successful examples. It is obvious that major progress in this area is primarily derived of recent advances in all aspects of science. Molecular modeling, X‐ray crystallography, and high field NMR have greatly contributed to this endeavor. Peptidomimetic inhibitors were traditionally developed by modifying peptide bonds, by mimicking the transition states for enzyme‐catalyzed reactions, or by constraining the conformational mobility of a peptide‐derived chain; the latter was used to overcome some of the pharmacokinetic barriers encountered in using peptides as drugs. Lately, these difficulties have been partially solved with rational drug design ofde novocompounds. Several methods have been successfully applied, with noteworthy examples currently in clinical trials, and many others are expected in the near future. It would be wrong, however, to imply that this process is a universal panacea. New ideas are urgently needed to produce clinical candidates faster and to solve some of the undesired pharmacokinetic issues.
Approaches to the Rational Design of Enzyme Inhibitors
Authors: McLeish Michael J. , Kenyon George L. 
Published: November 2003

AbstractSelective inhibitors of enzyme‐catalyzed reactions are widely used in both biochemical and medical science. The inhibitor may be used to block either a single enzyme or a metabolic pathway. The utility of an enzyme inhibitor as a mechanistic probe or a therapeutic agent will depend, in part, on the potency of the inhibitor and its specificity toward its target enzyme. These properties will, in turn, depend on the number and type of interactions the inhibitor makes with the enzyme and the overall mode of inhibition. Here we provide a concise overview of the forces involved in inhibitor binding, and a brief summary of the treatment of enzyme kinetic data. Enzyme inhibitors have been divided into two groups, reversible and irreversible, based on whether the inhibitor binds covalently to its target enzyme. Within these groups inhibitors have been classified on the basis of kinetics, structure, and mechanism. Examples are provided in all cases and, where possible, these are of inhibitors possessing therapeutic interest. The criteria for inclusion in each class of inhibitor are described, as well as the kinetic implications, with particular reference to the specificity of the inhibition. Treatment of the examples includes discussion of the design aspects and, if appropriate, a historical perspective that demonstrates the development of a rational approach to inhibitor design.
Chirality and Biological Activity
Authors: Draffan Alistair G. , Evans Graham R. , Henshilwood James A. 
Published: November 2003

AbstractThroughout the past two decades, the relationship between chirality and biological activity has become an area of vital importance to medicinal chemists in both the design and synthesis of novel small molecules. In this chapter, the definition of chirality and its biological implications are covered. The synthetic, chromatographic, and crystallization approaches to single isomer compounds are discussed with reference to the differing biological activities exhibited by stereoisomers.
Structural Concepts in the Prediction of the Toxicity of Therapeutical Agents
Authors: Rosenkranz Herbert S. 
Published: November 2003

Abstract
Currently available substructure‐based structure‐activity relationship (SAR) methodologies, if expertly used, can be employed to predict the toxicological potential of therapeutic agents. Moreover, with robust SAR models of toxicological phenomena, it is feasible to understand the basis of these toxicities and to ascertain their relevance to possible human health risks. At present, SAR approaches to the evaluation of toxicity must be used in conjunction with human expert knowledge. The currently available technology can be used to design molecules of reduced toxicity which retain their therapeutic effectiveness.
Natural Products as Leads for New Pharmaceuticals
Authors: Buss A. D. , Cox B. , Waigh R. D. 
Published: November 2003

AbstractA review of the use of natural products as starting points in the search for new pharmaceuticals, covering the broad areas of “Drugs affecting the centeral nervous system, ” “Neuromuscular blocking drugs,” “Anticancer drugs,” “Marine sources,” “Antibiotics,” “Cardiovascular drugs,” “Antiasthma drugs,” and “Antiparasitic drugs.” The review covers more than 100 years of development, from “old” drugs, such as morphine and quinine, to very recent discoveries, such as conotoxin and galantamine, and includes a discussion of the attributes of natural products as leads in the drug discovery process. Between 1990 and 2000, a total of 41 drugs derived from natural products were launched on the market by major pharmaceutical companies. In the chosen examples, the process of drug development is traced from the discovery of the activity of the natural compound, through chemical modification and biological evaluation, to either success or failure as a clinical product, highlighting the very different pathways to innovation that occur in each product.
High‐Throughput Screening for Lead Discovery
Authors: Houston John G. , Banks Martyn N. 
Published: November 2003

AbstractHigh‐throughput screening is now an integral part of the early drug discovery process. This high capacity technology addresses the need to screen large numbers of biological targets against large numbers of compounds to find starting points for medicinal chemistry programs. Over the last decade, technological innovation, integrated automation, and novel biological reagents have been combined to create high‐throughput screening systems. This technology connects disease targets of interest with large arrays of test compounds to enable the discovery of potential new drug candidates. The process of bioassay design, screen construction, hit identification, and compound profiling is the basic backbone of the lead discovery process. It is underpinned by a set of large scale, novel technologies that provide a seamless, highly efficient discovery process.
Application of Recombinant
DNA
Technology in Medicinal Chemistry and Drug Discovery
Authors: Basu Soumitra , Oyelere Adegboyega K. 
Published: November 2003

Abstract
Drug discovery is usually a long and arduous process. However, pharmaceutical industries are making a significant progress in simplifying certain aspects of drug discovery process, especially in the area of target discovery, validation, and lead‐compounds discovery. Advances in recombinant DNA technology are intimately connected with the explosion of newly identified pharmaceutically important targets, and an understanding of how these targets function to regulate biological processes of interest. This is providing new and exciting opportunities for therapeutic intervention in diseases including those diseases that were thought to be untreatable a few years back. In this chapter we describe how each stage of drug discovery, from target identification to lead generation and even clinical trials, have benefited from the tools of recombinant DNA technology.
Therapeutic Agents Acting on RNA Targets
Authors: Rife Jason P. 
Published: November 2003

Abstract
There are many therapeutics that target RNA, such as streptomycin, gentamicin, tetracycline; some of them have been around for years. All of them bind to ribosomal RNA and alter normal ribosome function. The modern strategies of drug discovery and design pertain nearly exclusively to protein targets. However, the field of drug discovery for RNA targets is maturing rapidly, largely because of the exciting ribosome/drug complexes that have recently been solved. Potential RNA drug targets abound for bacteria, viral, and cellular systems. Nevertheless, questions remain as to whether or not compounds can be found that simultaneously satisfy RNA binding and pharmacological properties, such as absorption and membrane permeation. The range of interactions observed, from Coulombic to hydrophobic, and the predicted “drug‐like” qualities of several ribosome binding antibiotics suggest that the discovery of drugs that target RNA can be a general phenomenon.
Allosteric Proteins and Drug Discovery
Authors: Bell J. Ellis , Burnett James C. , Bell Jessica K. , Galatin Peter S. , Abraham Donald J. 
Published: November 2003

Abstract
The existence of allosteric phenomena in the control of proteins allows for exquisite control of many of the cell's normal processes. Allosteric interactions involve the binding of an “allosteric” ligand to a site other than the functional (active) site of the protein, with a concomitant alteration in activity. Two major theoretical models have been presented to explain allosteric interactions, that of Monod, Wyman, and Changeux and that of Koshland, Nemethy, Filmer, Dalziel, and Engel. Although there are essential differences between the two models, both require that allosteric ligands interact with one or more forms of the protein to trigger a modulating effect. In only a few cases is much structural detail known about more than one conformational state of any given allosteric protein, or how the binding of small molecule effectors to an allosteric site triggers protein modulation. In this review the essential features of allosteric enzymes and allosteric models are examined in a context that leads to consideration of how drugs may be designed such that they either mimic or block normal allosteric effects. Several existing “allosteric” drugs, and a number of potential targets for the rationale design of future allosteric drugs, are discussed.
Receptor Targets in Drug Discovery and Development
Authors: Williams Michael , Mehlin Christopher , Triggle David J. 
Published: November 2003

Abstract

Drug discovery has entered a new century with an unheralded wealth of sophisticated technologies and information generation platforms, including the draft map of the human genome, which theoretically will allow the more rapid development of medicines with improved selectivity and safety profiles. To use the bewildering exponential flow of data related to the molecular targets involved in the cause(s) of various diseases and the increasingly sophisticated computer‐based technologies that define the requirements for chemical diversity and diversity space requires an understanding of basic receptor/enzyme theory. The latter, based on the Law of Mass Action, defines the concepts of agonism, antagonism, and more recently, allosteric modulation. The application of receptor/enzyme theory to the practical aspects of lead compound identification and optimization is based on defining structure‐activity relationships (SARs) for a variety of physiological and pharmacological parameters and involves the evaluation of new chemical entities in
in vitro
and
in vivo
assays that measure efficacy, selectivity, side effect liability and absorption, distribution, metabolism and excretion, and toxicology. Understanding how knowledge of drug targets has evolved; the challenges to validating new targets, especially those evolving from the genome; and assays beyond high‐throughput screening that provide objective SAR information, as well as designing compounds to interact with these targets that have “druggable” characteristics, are the keys to successful, and by definition, financially viable, drug discovery.
Nicotinic Acetylcholine Receptors
Authors: Colquhoun David , Shelley Chris , Hatton Chris , Unwin Nigel , Sivilotti Lucia 
Published: November 2003

Abstract

Nicotinic receptors are cation‐permeable ion channels activated by the neurotransmitter acetylcholine. The muscle‐type receptor mediates all fast synaptic excitation on voluntary muscle. We review both the structure and the function of muscle/
Torpedo
receptor, and the function of several mutants. Recent developments both in knowledge of structure and in analysis of single‐channel records are beginning to throw light on the role of single amino acid residues in the molecular events (the binding of an agonist and the gating of the channel) that lead to channel opening. In the nervous system, nicotinic channels mediate the majority of fast excitation only in autonomic ganglia, but are also present at presynaptic locations. Issues of receptor classification and subunit composition are particularly relevant for neuronal channels because of the numerous subunit combinations possible and because relatively few selective competitive antagonists are available, a situation that may improve with the characterization of alpha‐conotoxins. Inherited mutations in nicotinic channels give rise to rare congenital forms of human disease (myasthenia for muscle and epilepsy for neuronal receptors).
Analog Design
Authors: Cannon Joseph G. 
Published: November 2003

Abstract
The chapter addresses the design of nonprotein, nonpeptide drug analogs. Strategies and applications of classical and nonclassical bioisosteres, rigid and semirigid analogs; homologation of alkyl chains; changes in ring size and ring‐position isomers; substitution of aromatic for aliphatic rings; alteration of stereochemistry; design of fragments of lead molecules; and variation of interatomic distances are discussed. Numerous examples from the literature of each type of molecular modification are presented, together with summaries of pharmacological consequences of the modifications. Advantages and disadvantages of each category are cited.
Large‐Scale Synthesis
Authors: Gupton Frank , Grozinger Karl 
Published: November 2003

Abstract
The capability to fulfill drug substance requirements in support of the various elements of pharmaceutical development is an essential component of the overall drug development process. The preparation of bulk materials for toxicology, formulation development, and clinical supplies can represent a significant challenge, depending on such factors as the molecular complexity of the drug candidate, the quantities of materials required, and the state of development of the synthetic process. As a drug candidate proceeds through the various stages of drug development and into commercial launch, the challenge of process development is to ensure the uninterrupted supply of drug substance without compromising the ability to ultimately supply a commercially viable chemical process. This chapter serves to provide a general overview of the issues and requirements associated with the development and scale‐up of chemical processes for bulk active drug substances. An account of the nevirapine process development efforts at Boehringer Ingelheim is also provided as an example of the evolution of a chemical process from the initial efforts in medicinal chemistry through to commercial‐scale operations.
Metabolic Considerations in Prodrug Design
Authors: Balant Luc P. 
Published: November 2003

AbstractThis review concentrates on prodrugs designed by pharmaceutical chemists to overcome biopharmaceutical or pharmacokinetic (essentially metabolic) problems encountered with active principles. The investigations presented in this review illustrate the types of problems pharmaceutical chemists have tried to solve and the metabolic, kinetic, or biopharmaceutical rationale behind these attempts. Although very little published information is available on pharmacokinetic methods useful in the study of prodrugs and on the regulatory requirements needed for prodrug development, the authors have tried to develop some general ideas that might be useful in this regard.
Drug Discovery: The Role of Toxicology
Authors: Moe James B. , McKim James M. 
Published: November 2003

Abstract
This chapter describes the principles of toxicology in the context of rational application of toxicology and related disciplines in the discovery of new therapeutic agents. Fundamental types of mechanisms involved in the genesis of adverse effects produced by pharmaceutical agents on host organs, tissues, and cells are described. Various emerging technologies are presented as tools for use in the drug candidate selection and optimization processes to predict adverse effects and improve probability of discovery and development of new therapeutic agents.
Drug Absorption, Distribution, and Elimination
Authors: Benet Leslie Z. , Perotti Beatrice Y. T. , Hardy Larry 
Published: November 2003

Abstract
The chapter provides basic quantitative explanations of practical pharmacokinetic concepts that are key to understanding how drugs enter and depart from the body. The parameters that are discussed include hepatic and renal clearance, bioavailability, extraction ratio, half‐life, and volume of distribution. Relationships between these parameters are defined, and their utility for the design of dosing regimens to provide effective and nontoxic therapy is shown with some examples. The application of pharmacokinetics plays an essential role in the various preclinical and clinical phases of drug development, as well as in other areas such as environmental toxicology.
The FDA and Regulatory Issues
Authors: Rzeszotarski W. Janusz 
Published: November 2003

Abstract
A brief outline of information that is available on the Web pertinent to the FDA and regulatory issues. The process of new drug approval and its continuous modification reflects both the progress of science and the globalization of the world's economy. The reader is encouraged to follow the changes by constant monitoring of the FDA and the industry sites dedicated to these issues. The history of drug regulation in the United States, the evolving structure of the FDA, the steps to be taken in the process of obtaining the approval to market the new molecular entity, and the post‐approval requirements are briefly described.
Intellectual Property in Drug Discovery and Biotechnology
Authors: Kaba Richard A. , Maloney Timothy P. , Krueger James P. , Kratz Rudy , Tabin Julius 
Published: November 2003

AbstractIntellectual property is the branch of law that protects and, indeed, encourages the creation of certain products of the human mind or intellect. This chapter is intended to provide a basic understanding and appreciation of intellectual property law, especially as it relates to patents, trademarks, and trade secrets, in the United States and, to a lesser extent, in the remainder of the world. Issues and concerns particularly related to the drug discovery and development process are emphasized. By making effective use of the legal protection afforded by the intellectual property laws in the United States and elsewhere, the drug developer can protect its investment, enhance the value of the technology being developed, and earn a profit sufficient to allow and encourage further research into improving existing drugs and therapies as well as developing new drugs and therapies. By better understanding these intellectual property laws, the drug developer, together with experienced intellectual property counsel, can develop an effective intellectual property strategy. In this way, new and emerging technologies as well as new drug discoveries can be identified, managed, and protected as an integral part of an organization's research and development activities to create a strong intellectual property portfolio.
Myocardial Infarction Agents
Authors: Billman George E. , Altschuld Ruth A. 
Published: November 2003

AbstractA myocardial infarction begins with the occlusion of a coronary artery, usually resulting from the rupture of an atherosclerotic plaque. Pharmacologic treatment begins with conventional pain relief and under appropriate circumstances thrombolytic agents are administered. Anticoagulants are used in conjunction with thrombolytic agents to assist thrombolysis and prevent reocclusion of the affected vessel. Lethal arrhythmias such as ventricular fibrillation are a major cause of death following myocardial infarction. β‐Adrenoceptor antagonists are used to reduce the incidence of this sudden cardiac death. Angiotensin converting enzyme inhibitors are used to reduce post‐infarction ventricular remodeling, which is a leading cause of congestive heart failure.Current therapy has significantly reduced in hospital mortality but acute myocardial infarction remains the leading cause of death in the United States. Congestive heart failure secondary to myocardial infarction is becoming an epidemic. Additional therapeutic agents and/or strategies are needed to reduce death and disability following myocardial infarction.
Endogenous Vasoactive Peptides
Authors: Webb Randy L. , Ksander Gary M. 
Published: November 2003

AbstractThe control of vasomotor tone regulates the overall cardiovascular system and its responses to physiological and pathophysiological stress. It provides differential blood flow to regional vascular beds under normal physiologic conditions, at times of normal stress, such as exercise, and during conditions of pathological stress, such as congestive heart failure. Although the vascular system regulates many of its functions at the site of the blood vessel itself, other factors that may control vascular tone include the autonomic nervous system, circulating hormones functioning in an endocrine role, and reflex metabolic control. Many newly discovered peptides were found to be widespread in autonomic and sensory neurons innervating the vasculature, and they possess potent vasoactive effects on many blood vessels. Vasoactive peptides have been shown to play an important role in many pathological situations, for example, asthma, arthritis, vascular headaches, hypertension, and other cardiovascular diseases. In this chapter, we will outline the evidence for the different actions of various vasoactive peptides, their interaction with other systems, the possible role they have in diseases, and the present and future therapeutic use of vasoactive peptide agonists and antagonists.
Hematopoietic Agents
Authors: Harrington Maureen 
Published: November 2003

AbstractHematopoesis is a life‐long process that involves the continuous formation and turnover of blood cells. Maintaining adequate blood cell production, as well as being able to meet increased demand, is in part under the control of a group of hormone‐like glycoproteins that includes the hematopoietic growth factors and the interleukins. More specifically, the production of hematopoietic stem cell self‐renewal (giving rise to identical daughter cells) and production of the specific progenitor cells that are increasingly restricted in their developmental pathway are under the control of the hematopoietic growth factors and the interleukins. In the chapter, four cytokines approved by the Food and Drug Administration for use in humans are described; this is followed by a limited discussion of one cytokine, stem cell factor, that currently has orphan drug status and a brief description of two cytokines currently undergoing clinical evaluation. The field of cytokine research is always expanding as new interleukins are identified each year. As our understanding of the cell and molecular biology of cytokine action on hematopoiesis increases, the clinical use of these agents will become more refined.