This book comprehensively reviews the state-of-the-art strategies developed for protein-protein interaction (PPI) inhibitors, and highlights the success stories in new drug discovery and development. Consisting of two parts with twelve chapters, it demonstrates the design strategies and case studies of small molecule PPI inhibitors. The first part discusses various discovery strategies for small molecule PPI inhibitors, such as high throughput screening, hot spot-based design, computational approaches, and fragment-based design. The second part presents recent advances in small molecule inhibitors, focusing on clinical candidates and new PPI targets. This book has broad appeal and is of significant interest to the pharmaceutical science and medicinal chemistry communities.

This thesis mainly describes the development of a screening process for a mirror-image library of chiral natural products. It demonstrates how, by using mirror-image proteins for the screening of available natural products, unavailable mirror-image isomers of natural products can be screened in a mirror process. Moreover, as mirror-image isomers including target proteins and natural products are mainly prepared by means of chemical synthesis, the screening strategy presented here suggests the importance of organic chemistry. Natural products are commonly used as valuable resources for drug discovery. However, as they are mostly produced as single enantiomeric forms, researchers have tested o nly natural products bearing one stereochemistry available in nature. As natural products and their enantiomers have identical physicochemical properties and different biological activities, mirror-image isomers of natural products are promising candidates for novel medicinal resources. In an effort to identify anticancer agents from the mirror-image library, chemical protein syntheses of some target oncoproteins, MDM2, MDMX and Grb2, and their applications to the chemical array screening process were achieved. In the course of this process the NP843 enantiomer, which is the enantiomer of an -tocopherol derivative, was successfully identified as a novel MDM2-p53 interaction inhibitor. These results clearly show that a mirror-image library of chiral natural products represents an invaluable medicinal resource. Accordingly, the chemistry-based screening strategy described in this thesis will be of great interest to a broad range of chemists involved in natural product, medicinal, and synthetic chemistry.

This book is the first to be entirely devoted to the challenging art of handling membrane proteins out of their natural environment, a key process in biological and pharmaceutical research, but one plagued with difficulties and pitfalls. Written by one of the foremost experts in the field, Membrane Proteins in Aqueous Solutions is accessible to any member of a membrane biology laboratory. After presenting the structure, functions, dynamics, synthesis, natural environment and lipid interactions of membrane proteins, the author discusses the principles of extracting them with detergents, the mechanisms of detergent-induced destabilization, countermeasures, and recent progress in developing detergents with weaker denaturing properties. Non-conventional alternatives to detergents, including bicelles, nanodiscs, amphipathic peptides, fluorinated surfactants and amphipols, are described, and their relative advantages and drawbacks are compared. The synthesis and solution properties of the various types of amphipols are presented, as well as the formation and properties of membrane protein/amphipol complexes and the transfer of amphipol-trapped proteins to detergents, nanodiscs, lipidic mesophases, or living cells. The final chapters of the book deal with applications: membrane protein in vitro folding and cell-free expression, solution studies, NMR, crystallography, electron microscopy, mass spectrometry, amphipol-mediated immobilization of membrane proteins, and biomedical applications. Important features of the book include introductory sections describing foundations as well as the state-of-the-art for each of the biophysical techniques discussed, and topical tables which organize a widely dispersed literature. Boxes and annexes throughout the book explain technical aspects, and twelve detailed experimental protocols, ranging from in vitro folding of membrane proteins to single-particle electron cryomicroscopy, have been contributed by and commented on by experienced users. Membrane Proteins in Aqueous Solutions offers a concise, accessible introduction to membrane protein biochemistry and biophysics, as well as comprehensive coverage of the properties and uses of conventional and non-conventional surfactants. It will be useful both in basic and applied research laboratories and as a teaching aid for students, instructors, researchers, and professionals within the field.

This invaluable resource discusses the current revolution in stem cell-based drugs and their potential use in clinical applications. Each chapter is contributed by a pre-eminent scientist in the field. An introductory section presents current stem cell drugs and stem cell-based products and a discussion of production, quality control, mechanisms, and efficacy. Following sections include discussions on stem cell-derived microvesicles based products, and derived exosomes based products. Stem Cell Drugs - A New Generation of Biopharmaceuticals and the other books in the Stem Cells in Clinical Applications series are invaluable to scientists, researchers, advanced students and clinicians working in stem cells, regenerative medicine or tissue engineering. This groundbreaking volume is also essential reading for those researching or studying drug development or pharmaceutical science.

This book studies the production of indole alkaloids in the important medicinal plant Catharanthus roseus (L.) G. Don, commonly known as periwinkle. The anticancer alkaloids, viz. vinblastine and vincristine, are mainly present in the leaves of C. roseus and inhibit the growth of cancer cells by hindering the formation of mitotic apparatus during cell division. Further, vinblastine helps increase the chance of surviving childhood leukemia while vincristine is used to treat Hodgkin's disease. Great efforts have been made to produce these alkaloids at a large scale by the culture of plant cells. In view of this worldwide demand for commercial use, this book explores how to maximize the production of anticancer alkaloids from C. roseus. This reference book will be helpful for research students, teachers, ethnobotanists, pharmacologists and herbal growers who have a strong interest in this anticancer medicinal plant of paramount importance.

This book draws on medical sociology and science and technology studies to develop a novel conceptual framework for understanding innovation processes, using the case study of deep brain stimulation in paediatric neurology. It addresses key questions, including: How are promising and potentially disruptive new health technologies integrated into busy resource-constrained clinical contexts? What activities are involved in establishing a new clinical service? How do social and cultural forces shape these services, and importantly, how are understandings of 'health' and 'illness' reconfigured in the process? The book explores how the ideals of patient-centred medicine influence innovation in the clinic, and it introduces the concept of patient-centred proto-platforms. It argues that patient-centred innovation can constitute an expansion of medical power, as the clinical gaze is directed not only towards the body but also towards the patient as a social being. This will be an innovative and insightful read for academics and advanced students, as well as health service researchers with an interest in technology adoption processes.

The book covers theoretical background and methodology as well as all current applications of Quantitative Structure-Activity Relationships (QSAR). Written by an international group of recognized researchers, this edited volume discusses applications of QSAR in multiple disciplines such as chemistry, pharmacy, environmental and agricultural sciences addressing data gaps and modern regulatory requirements. Additionally, the applications of QSAR in food science and nanoscience have been included - two areas which have only recently been able to exploit this versatile tool. This timely addition to the series is aimed at graduate students, academics and industrial scientists interested in the latest advances and applications of QSAR.

Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors

This fully updated new edition presents organic reaction mechanism questions, carefully selected from the primary chemical literature, to understand how reactants are transformed into products. The author explains step-by-step solutions to all problems with appropriate contextual comments explaining the rationale and reasoning underlying each step, and identifying the underlying principles involved in each question. In the process the reader gains a better understanding of the fundamental principles of organic chemistry and how to become proficient in using the Lewis acid/Lewis base concept to complete organic reactions without resorting to memorization. Features : The questions are graded in difficulty with Part A containing questions aimed at students taking the sophomore-level organic chemistry class, while part B contains questions of somewhat greater difficulty suitable for students taking an honors course in organic chemistry or a beginning graduate course. Detailed answers are provided to all questions so students can check their answers and important points are highlighted in each answer. Special emphasis has been placed on the selection of questions to ensure that each question illustrates one or more fundamental principles of organic chemistry. Interspersed throughout the book are minireviews that cover the material pertaining to a particular topic. The specific literature references corresponding to each question are included and students can look up those references for more contextual information. Includes a large number of carefully-selected mechanism questions and step-by-step solutions, including explanatory comments

The first contribution describes apolar and polar molecular fossils and, in particular biomarkers, along the lines usually followed in organic chemistry textbooks, and points to their bioprecursors when available. Thus, the apolar compounds are divided in linear and branched alkanes followed by alicyclic compounds and aromatic and heterocyclic molecules, and, in particular, the geoporphyrins. The polar molecular fossils contain as functional groups or constituent units ethers, alcohols, phenols, carbonyl groups, flavonoids, quinones, and acids, or are polymers like kerogen, amber, melanin, proteins, or nucleic acids. The final sections discuss the methodology used and the fundamental processes encountered by the biomolecules described, including diagenesis, catagenesis, and metagenesis. The second contribution covers the distribution of phthalides in nature and the findings in the structural diversity, chemical reactivity, biotransformations, syntheses, and bioactivity of natural and semisynthetic phthalides.

The objective of this volume is to consolidate within a single text the most current knowledge, practical methods, and regulatory considerations pertaining to formulations development with poorly water-soluble molecules. A pharmaceutical scientist's approach toward solubility enhancement of a poorly water-soluble molecule typically includes detailed characterization of the compound's physiochemical properties, solid-state modifications, advanced formulation design, non-conventional process technologies, advanced analytical characterization, and specialized product performance analysis techniques. The scientist must also be aware of the unique regulatory considerations pertaining to the non-conventional approaches often utilized for poorly water-soluble drugs. One faced with the challenge of developing a drug product from a poorly soluble compound must possess at minimum a working knowledge of each of the abovementioned facets and detailed knowledge of most. In light of the magnitude of the growing solubility problem to drug development, this is a significant burden especially when considering that knowledge in most of these areas is relatively new and continues to develop

This volume serves as a valuable handbook for the development of nanomedicines made of polymer nanoparticles because it provides researchers, students, and entrepreneurs with all the material necessary to begin their own projects in this field. Readers will find protocols to prepare polymer nanoparticles using different methods, since these are based on the variety of experiences that experts encounter in the field. In addition, complex topics such as, the optimal characterization of polymer nanoparticles is discussed, as well as practical guidelines on how to formulate polymer nanoparticles into nanomedicines, and how to modify the properties of nanoparticles to give them the different functionalities required to become an efficient nanomedicine for different clinical applications. The book also discusses the translation of technology from research to practice, considering aspects related to industrialization of preparation and aspects of regulatory and clinical development.

Antisense-based drugs are part of a growing number of pharmaceutical and biotech programs to treat diseases including cancer, diabetes, and ALS. Reviewing fundamentals and offering guidelines for drug discovery and development, this book is a practical guide from the safety assessment to clinical experience with antisense oligonucleotides. Examines principles and tools for scientists in both pre-clinical and clinical settings and how to apply them to antisense oligonucleotides Reviews fundamentals and provides guidelines for scientists in drug design and discovery to increase efficiency, assessment, and success of drug candidates Helps readers understand antisense molecules and their targets, biochemistry and toxicity mechanisms, roles in disease, and applications for safety and therapeutics Includes interdisciplinary perspectives, from both academia and research, on a hot topic that combines pharmacology, toxicology, biology, and medicinal chemistry to advance our understanding and application of therapeutics

While systems biology and pharmacodynamics have evolved in parallel, there are significant interrelationships that can enhance drug discovery and enable optimized therapy for each patient. Systems pharmacology is the relatively new discipline that is the interface between these two methods. This book is the first to cover the expertise from systems biology and pharmacodynamics researchers, describing how systems pharmacology may be developed and refined further to show practical applications in drug development. There is a growing awareness that pharmaceutical companies should reduce the high attrition in the pipeline due to insufficient efficacy or toxicity found in proof-of-concept and/or Phase II studies. Systems Pharmacology and Pharmacodynamics discusses the framework for integrating information obtained from understanding physiological/pathological pathways (normal body function system vs. perturbed system due to disease) and pharmacological targets in order to predict clinical efficacy and adverse events through iterations between mathematical modeling and experimentation.

Leading researchers are specially invited to provide a complete understanding of a key topic within the multidisciplinary fields of physiology, biochemistry and pharmacology. In a form immediately useful to scientists, this periodical aims to filter, highlight and review the latest developments in these rapidly advancing fields.

In this volume, the specific challenges and problems facing the evaluation of new oncology agents are explored with regards to pharmacokinetic, pharmacodynamic modeling and clinical pharmacology development strategies. This book delivers, with an emphasis on the oncology therapeutic area, the goals set in the first three volumes: namely - to provide clinical pharmacologists practical insights for the application of pharmacology, pharmacokinetics and pharmacodynamics for new drug development strategies. Pharmacokinetic-pharmacodynamic concepts for tyrosine kinases, the evaluation of cardiac repolarization prolongation through QTc interval effects, efficacy- and safety-response analyses to support new drug approvals, clinical and preclinical tumor growth modeling, and flat- vs weight-based dose selection are showcased from an oncology clinical pharmacologist's point-of-view. Oncology development strategies are surveyed for new FDA-approvals to identify patterns in expectations at time of first approval. The special considerations necessary to address combination drug development, metronomics, biosimilars and breakthrough therapies are also presented.

This book offers a high-level treatise of evidence-based decisions in drug development. Because of the inseparable relationship between designs and decisions, a good portion of this book is devoted to the design of clinical trials. The book begins with an overview of product development and regulatory approval pathways. It then discusses how to incorporate prior knowledge into study design and decision making at different stages of drug development. The latter include selecting appropriate metrics to formulate decisions criteria, determining go/no-go decisions for progressing a drug candidate to the next stage and predicting the effectiveness of a product. Lastly, it points out common mistakes made by drug developers under the current drug-development paradigm. The book offers useful insights to statisticians, clinicians, regulatory affairs managers and decision-makers in the pharmaceutical industry who have a basic understanding of the drug-development process and the clinical trials conducted to support drug-marketing authorization. The authors provide software codes for select analytical approaches discussed in the book. The book includes enough technical details to allow statisticians to replicate the quantitative illustrations so that they can generate information to facilitate decision-making themselves.

The content of this book is intended to provide the toxicologist in drug development in the pharmaceutical and biotechnology industries with a broad understanding of bone and its interactions with other organ systems in safety assessments. The book is divided into three parts. The first part describes our current understanding of bone biology and its primary regulatory pathways. Additional chapters address regulatory and study design considerations for incorporating bone end points in toxicology studies, with special consideration being given to juvenile toxicology studies. This is intended to address recent regulatory requirements to evaluate skeletal development for drugs in development for pediatric populations. The second part of the book describes the principal techniques and methods used in bone research; understanding how these end-points are derived is fundamental to their appropriate application. These first two parts of the book provide the background and the means to develop the concepts in part three which describes bone and its interaction with other organ systems. The unique series of chapters in part three, contributed to by key leaders in their respective fields and in bone research, provides a comprehensive collective work. Although constantly evolving, the crosstalk and interaction of the skeleton with several organ systems is now recognized and well documented, such as for the reproductive system, muscle and kidney, while our understanding of the interaction with other organ systems, such as the immune system and CNS, is in its infancy. Recent work highlights the key role of the skeleton in the regulation of energy metabolism and the impact this has on research in metabolic diseases such as obesity and diabetes. The hope is that this book will enlighten many and encourage more to explore the impact of new compounds on the skeleton in the development of effective and safe drugs.

The first contribution reviews the occurrence of xanthine alkaloids in the plant kingdom and the elucidation of the caffeine biosynthesis pathway, providing details of the N-methyltransferases, belonging to the motif B' methyltransferase family which catalyze three steps in the four step pathway leading from xanthosine to caffeine. The second contribution in this book provides a background on the molecule and related compounds and update knowledge on the most recent advances in Iboga alkaloids. The third contribution presents a comprehensive analysis of frequently occurring errors with respect to 13C NMR spectroscopic data and proposes a straightforward protocol to eliminate a high percentage of the most obvious errors.

This book describes how microbes can be used as effective and sustainable resources to meet the current challenge of finding suitable and economical solutions for biopharmaceuticals, enzymes, food additives, nutraceuticals, value added biochemicals and microbial fuels, and discusses various aspects of microbial regulatory activity and its applications. It particularly focuses on the design, layout and other relevant issues in industrial microbe applications. Moreover, it discusses the entire microbial-product supply chain, from manufacturing sites to end users, both in domestic and international markets, providing insights into the global marketing of microbes and microbial biomass-derived products. Further, it includes topics concerning the effective production and utilization of eco-friendly biotechnology industries. It offers a valuable, ready-to-use guide for technologists and policymakers developing new biotechnologies.

This consolidated reference book addresses the various aspects of nano biomaterials used in ophthalmic drug delivery, including their characterization, interactions with ophthalmic system and applications in treatments of the ophthalmic diseases and disorders. In the last decade, a significant growth in polymer sciences, nanotechnology and biotechnology has resulted in the development of new nano- and bioengineered nano-bio-materials. These are extensively explored as drug delivery carriers as well as for implantable devices and scaffolds. At the interface between nanomaterials and biological systems, the organic and synthetic worlds merge into a new science concerned with the safe use of nanotechnology and nano material design for biological applications. For this field to evolve, there is a need to understand the dynamic forces and molecular components that shape these interactions. While it is impossible to describe with certainty all the bio physicochemical interactions at play at the interface, we are at a point where the pockets of assembled knowledge are providing a conceptual framework to guide this exploration, and review the impact on future product development. The book is intended as a valuable resource for academics and pharmaceutical scientists working in the field of polymers, polymers materials for drug delivery, drug delivery systems and ophthalmic drug delivery systems, in addition to medical and health care professionals in these areas.

This book provides information on best practices and new thinking regarding the validation of alternative methods for toxicity testing. It covers the validation of experimental and computational methods and integrated approaches to testing and assessment. Validation strategies are discussed for methods employing the latest technologies such as tissue-on-a-chip systems, stem cells and transcriptomics, and for methods derived from pathway-based concepts in toxicology. Validation of Alternative Methods for Toxicity Testing is divided into two sections, in the first, practical insights are given on the state-of-the-art and on approaches that have resulted in successfully validated and accepted alternative methods. The second section focuses on the evolution of validation principles and practice that are necessary to ensure fit-for-purpose validation that has the greatest impact on international regulatory acceptance of alternative methods. In this context validation needs to keep pace with the considerable scientific advancements being made in toxicology, the availability of sophisticated tools and techniques that can be applied in a variety of ways, and the increasing societal and regulatory demands for better safety assessment. This book will be a useful resource for scientists in the field of toxicology, both from industry and academia, developing new test methods, strategies or techniques, as well as Governmental and regulatory authorities interested in understanding the principles and practicalities of validation of alternative methods for toxicity testing.

This book describes 200 bio-polymers, including the most recent and advanced nanotechnology applications. The applications of various bio-medical and other future potential uses are covered and examined in depth. Systematic discussion of current leading natural polymers is also included.

Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors.

This book addresses the issues relating to a wide variety of ocular diseases from which millions of people suffer. Long-term challenges include visual impairment and ocular blindness. Certain ocular diseases are quite rare, whereas others, such as cataracts, age-related macular degeneration (AMD), and glaucoma, are very common, especially in the aging population. A rapid expansion of new technologies in ocular drug delivery and new drug candidates, including biologics, to treat these challenging diseases in the retina and posterior segments of the eye have recently emerged. These approaches are necessary because the eye has many unique barriers to drug delivery. Thus, this timely reference Drug Delivery for the Retina and Posterior Segment Disease compiles and analyzes recent advances in the research and development of drug delivery systems for retina and posterior segment diseases of the eye, with an emphasis on the use of implantable devices, iontophoresis as well as micro- and nanoparticles.