Zinc Enzyme Inhibitors

Brings together functional and structural informationrelevant to the design of drugs targeting zinc enzymes The second most abundant transition element in living organisms, zinc spans all areas of metabolism, with zinc-containing proteins offering both established and potential drug targets. Drug Design of Zinc-Enzyme Inhibitors brings together functional and structural information relevant to these zinc-containing targets. With up-to-date overviews of the latest developments field, this unique and comprehensive text enables readers to understand zinc enzymes and evaluate them in a drug design context. With contributions from the leaders of today's research, Drug Design of Zinc-Enzyme Inhibitors covers such key topics as: Major drug targets like carbonic anhydrases, matrix metalloproteinases, bacterial proteases, angiotensin-converting enzyme, histone deacetylase, and APOBEC3G Roles of recently discovered zinc-containing isozymes in cancer, obesity, epilepsy, pain management, malaria, and other conditions Cross reactivity of zinc-enzyme inhibitors and activators The extensive use of X-ray crystallography and QSAR studies for understanding zinc-containing proteins Clinical applications An essential resource for the discovery and development of new drug molecules, Drug Design of Zinc-Enzyme Inhibitors gives researchers, professionals, students, and academics the foundation to understand and work with zinc enzyme inhibitors and activators.

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 research aimed to synthesize and characterize Zn2+-ligand complexes that have the same zinc coordination environment as in histone deacetylase (HDAC) and other important zinc dependent enzymes. Mimicking the structural and the functional properties of Zn2+-enzymes will allow us to understand the binding reactivity between Zn2+ and small molecule enzyme inhibitors. The new understanding will help to develop new approaches to target disease states such as cancer. A variety of Zn2+ binary complexes have been synthesized and their interactions with inhibitors such as suberanilohydroxamic acid (SAHA) and 8-Hydroxyquinoline (8HQ) have been studied using 1H NMR, UV-Vis, and fluorescence spectroscopies. Attempts were made to mimic the structure of Zn2+-metalloenzyme active sites by exploring several different supporting ligands to model enzyme active sites. We endeavored to mimic an "O2N" ligand set of HDAC by using reported Zn2+-complexes ligated by Bis(phenolato)amine (H2L1), Bis(2-picolyl) amine (BPA, L2), hydrotris(3-phenyl-5-methylpyrazol-1-yl) (TpPh,Me, L3), and a similar neutral ligand (L4). The binding constants of the ligands with zinc were estimated using UV-Vis studies and calculations based on equilibrium expressions. This data was compared with previously reported data using other methods such as potentiometry and isothermal titration calorimetry. Once the zinc-ligand complexes were obtained, they were examined for mimicking zinc active sites. Attempts were made to study the interaction of inhibitors with the zinc center using 1H NMR, UV-Vis, and fluorescence spectroscopies. In addition, the functional properties of the mimicked structure were explored by attempting to cleave the amide group of a model substrate for HDAC, N-acetylbenzylamine. Although the Zn2+ species were not active, Al 3+ was observed to cleave the amide group at high temperature after extended periods of time. The zinc-ligand 9 structures were also examined using computational methods to support the experimental data. The results of this work are valuable complementary data to previously reported ITC data and the known biological systems.

This volume is the newest release in the authoritative series issued by the National Academy of Sciences on dietary reference intakes (DRIs). This series provides recommended intakes, such as Recommended Dietary Allowances (RDAs), for use in planning nutritionally adequate diets for individuals based on age and gender. In addition, a new reference intake, the Tolerable Upper Intake Level (UL), has also been established to assist an individual in knowing how much is "too much" of a nutrient. Based on the Institute of Medicine's review of the scientific literature regarding dietary micronutrients, recommendations have been formulated regarding vitamins A and K, iron, iodine, chromium, copper, manganese, molybdenum, zinc, and other potentially beneficial trace elements such as boron to determine the roles, if any, they play in health. The book also: Reviews selected components of food that may influence the bioavailability of these compounds. Develops estimates of dietary intake of these compounds that are compatible with good nutrition throughout the life span and that may decrease risk of chronic disease where data indicate they play a role. Determines Tolerable Upper Intake levels for each nutrient reviewed where adequate scientific data are available in specific population subgroups. Identifies research needed to improve knowledge of the role of these micronutrients in human health. This book will be important to professionals in nutrition research and education.

With chapter contributions from more than 30 metal biology experts, Cellular and Molecular Biology of Metals explains the role of key divalent metal ions involved in the molecular and cellular biology of various target cell populations. Although it primarily focuses on homeostatic metals, such as nickel, zinc, and chromium, the text also discusses

Carbonic Anhydrase: Its Inhibitors and Activators provides a state-of-the-art overview of the latest developments and challenges in carbonic anhydrase research. Authors describe the mechanisms of action of specific inhibitors in relation to physiological function, and present previously unpublished research on CA activators. Written by a team of in

Papers presented at a meeting held in San Miniato (Pisa), Italy, June 17-22, 1985.

This book offers deep insights into the thermodynamics and molecular structures of the twelve catalytically active isoforms of human carbonic anhydrase (CA) with a particular focus on inhibitor binding for drug design. X-ray crystallographic structures in combination with enzyme kinetic testing provide information on the interaction of CAs and their inhibitors, knowledge which is crucial for rational drug design. CAs are zinc carrying enzymes that catalyse the reversible interconversion of carbon dioxide and bicarbonate and are involved in numerous cellular processes. They are therefore a common target for drugs. The suppression of CA activities through inhibitory compounds has found application for example in diuretics and in glaucoma therapy. In this book methods used to determine binding thermodynamics of inhibitory compounds (Isothermal titration calorimetry, Fluorescent thermal shift assay/differential scanning fluorimetry and others) will be compared in detail. Also types and chemical synthesis of CA inhibitors, the use of antibodies against CAs as well as inhibitor application in animals are discussed.

The zinc metalloproteases are a diverse group of enzymes which are becoming increasingly important in a variety of biological systems. Their major function is to break down proteins. This text presents recent research results on the biochemistry and molecular biology of these enzymes.

Metal ions in biology is an ever expanding area in science and medicine involving metal ions in proteins and enzymes, their biosynthesis, catalysis, electron transfer, metal ion trafficking, gene regulation and disease. While X-ray crystallography has provided snapshots of the geometric structures of the active site redox cofactors in these proteins, the application of high resolution EPR spectroscopy in conjunction with quantum chemistry calculations has enabled, in many cases, a detailed understanding of a metalloenzymes mechanism through investigations of the geometric and electronic structure of the resting, enzyme-substrate intermediates and product complexes. This volume, Part II of a two-volume set demonstrates the application of high resolution EPR spectroscopy in determining the geometric and electronic structure of active site metal ion centers in iron sulfur cluster containing metalloproteins, mononuclear molybdenum metalloenzymes, manganese-containing enzymes and novel metalloproteins.