bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemical Libraries: Screening for Biologically Active Small Molecules
Authors: Schuffenhauer Ansgar 
Published: February 2008

AbstractThe screening of chemical libraries is one of the major sources for new leads in drug discovery. The large size of chemistry space compared with the library sizes that are feasible to screen requires careful selection of the compounds for the screening library to maximize screening success. Besides issues around technology compatibility and chemical tractability of the compounds, the main objective is to increase the probability of obtaining hits for the screened targets. Diversity selection approaches have often shown only limited success. In the absence of any knowledge, it is proposed to screen smaller “lead‐like” ligands with preference. When knowledge about the target is available, it can be used for target‐focused compound selection or for library design. In the screening process, physical high‐throughput screening (HTS) can be combined with virtual screening either to avoid the high‐throughput primary screen of the whole library or to limit false negatives by combining primary HTS and virtual screening results. Screening an initial subset then using the results obtained to predict likely hits for subsequent screening rounds in sequential screening can lessen the number of compounds to be screened, but it causes a greater logistics effort and has the risk of missing compounds that are not well represented structurally by the initial set. Data analysis and visualization of the screening results are a necessary final step of a screening campaign to ensure that the prioritization of compounds followed up is based on all available relevant information.
Collagen Triple Helix: Stability
Authors: Bächinger Hans Peter , Mizuno Kazunori 
Published: February 2008

AbstractCollagens are the most abundant extracellular matrix proteins in multicellular animals. They all contain a name‐giving collagen triple helix, which connects their three chains and varying amounts of other noncollagenous protein domains. To form the triple helix a repeated sequence of ‐Gly‐Xaa‐Yaa‐ is required, where Xaa and Yaa can be any residue. Each chain forms a polyproline‐II like left‐handed helix. The three chains are staggered by one residue from each other, and form a right‐handed helix. Twenty eight types of collagen molecules have been identified in mammals. The stability of the collagen triple helix is based on the length and the amino acid sequence of each polypeptide chain, and also by the presence of interchain cross‐links and/or trimerization domains. The 4(R)‐hydroxylation of proline residues in the Yaa position significantly increases the stability of the collagen triple helix.
Cyclooxygenase Inhibition Mechanisms: Recent Advances
Authors: Turman Melissa V. , Blobaum Anna L. , Konkle Mary E. , Marnett Lawrence J. , Hancock A.B. 
Published: February 2008

AbstractCyclooxygenases (COXs) are key enzymes of bioactive lipid metabolism that catalyze the committed step in prostaglandin biosynthesis. Inhibition of COX catalysis is a principal mode of action of nonsteroidal antiinflammatory drugs (NSAIDs). The combination of structural and functional analysis of COX‐inhibitor interactions has provided important insights into the molecular determinants of inhibition. Although COX protein structure does not change significantly on inhibitor binding, a surprising variety of binding modes and molecular interactions are observed with different NSAIDs. This article focuses on recent advances in our understanding of these interactions with emphasis on arylcarboxylic acid‐based inhibitors and their derivatives.
Cytochrome P450 Monooxygenases, Chemistry of
Authors: Denisov Ilia G 
Published: February 2008

AbstractCytochromes P450 monooxygenases represent a large superfamily of heme enzymes, which require a dioxygen molecule and two electrons supplied by a NAD(P)H‐dependent protein redox partner to form catalytically active high‐valent ferryl‐oxo intermediate. These heme enzymes are found in most organisms from all biological kingdoms and catalyze various oxidative chemical transformations important for the biosynthesis of steroid hormones, vitamins, signaling molecules, and many other compounds, as well as for the metabolism of xenobiotics.
Small Molecule Inhibitors: Design and Selection
Authors: Che Jianwei , Liu, Yi , Gray Nathanael S. 
Published: February 2008

Abstract
The discovery and optimization of small‐molecule inhibitors for the treatment of human disease has been the major focus of the pharmaceutical industry for more than a century. In the last decade, they have also attracted increased attention from academia because they provide a powerful means to interrogate biologic systems in an acute fashion. Although pharmaceutical companies have identified many small‐molecule inhibitors for drug targets, to find a desirable small‐molecule inhibitor for a specific target is still a major challenge for drug discovery and for chemical biology. Here, we present an overview of the computational approaches that can be exploited to discover small‐molecule inhibitors for protein targets of interest.
Directed Evolution: Novel and Improved Enzymes
Authors: Wen Fei , McLachlan Michael , Zhao Huimin 
Published: February 2008

Abstract
By mimicking Darwinian evolution in the test tube, directed evolution has become a powerful tool for engineering novel enzymes for basic and applied biology research and medicine. Unlike structure‐based rational design, directed evolution is capable of altering single or multiple functional properties such as activity, specificity, selectivity, stability, and solubility of naturally occurring enzymes in the absence of detailed knowledge of enzyme structure, function, or mechanism. More recently, directed evolution has also been used to engineer metabolic pathways, viruses, and whole microorganisms, and to address fundamental problems in biology. The success of directed evolution has been largely fueled by the development of numerous molecular biology techniques that enable the creation of genetic diversity through random mutagenesis or homologous or nonhomologous recombination in the target genes and the development of powerful high throughput screening or selection methods as well as by novel applications. This review will highlight the key developments in directed evolution and focus on the design and engineering of novel enzymes through directed evolution and their implications in chemical biology.
DNA
Damage: Sensing
Authors: Yang Xiaohong H. , Zou Lee 
Published: February 2008

Abstract
Maintenance of genomic stability is essential for the survival of cells, organisms, and species. Genomic stability relies on the complete and accurate transmission of genetic materials from mother cells to daughter cells and from one generation to the next. This task is daunting, however, because the genome is constantly challenged by numerous intrinsic and extrinsic stresses that damage deoxyribonucleic acid (DNA). If left untreated, such damage can destabilize the genome by introducing gene mutations, duplications, and chromosomal rearrangements such as deletions and inversions, which fortunately does not normally happen as cells evolve a complex damage sensing and signaling mechanism named the DNA damage and replication checkpoint. Checkpoint activation effectively pauses the progression of the cell cycle, allowing more time for the removal of DNA lesion. Moreover, activated checkpoint also regulates and coordinates a number of cellular processes including DNA repair, DNA replication, and chromatin remodeling to alleviate the stress on the genome. At the core of the checkpoint‐signaling network, a family of phosphoinositide‐3‐kinase (PI‐3K)‐like kinases and their regulatory partners serve as both DNA damage sensors and initiators of checkpoint signaling. In this article, we will discuss in detail how DNA damage is sensed and processed by the DNA damage and replication checkpoint. We will also discuss how signals generated at sites of DNA damage are propagated and relayed through the checkpoint pathways to influence other cellular events.
Drug Transport in Living Systems
Authors: Elbaz Yael , Schuldiner Shimon 
Published: February 2008

Abstract
Living organisms are constantly assailed by a host of harmful chemicals from the environment. Because of the diversity of these “xenobiotics”, cellular survival mechanisms must deal with an immense variety of molecules. Polyspecific drug transporters supply one such strategy. They recognize a wide range of dissimilar substrates that may differ in structure, size, or electrical charge, and they actively remove them from the cytoplasm. As such, these transporters provide an essential survival strategy for the organism. However, given that the substrates of these multispecific transporters include many antibiotics as well as antifungal and anticancer drugs, they are associated with the phenomenon of multidrug resistance (MDR) that poses serious problems in the treatment of cancers and infectious diseases, and some of them are coined multidrug transporters (MDTs). As expected from their central role in survival, these transporters are ubiquitous, and in many genomes, several genes coding for putative MDTs have been identified. MDTs are found in evolutionary unrelated membrane transport protein families, which suggests that they might have developed independently several times during the course of evolution. In this review, we discuss some basic concepts regarding drug transport from bacteria to humans.
Endoplasmic Reticulum
Authors: Bánhegyi Gábor , Benedetti Angelo , Csala Miklós 
Published: February 2008

AbstractSeveral pathways are compartmentalized in the endoplasmic reticulum (ER). These intraluminal activities require the passage of substrates, cofactors, and products through the ER membrane. The arguments for a general permeability of the ER membrane are contradicted by strong biochemical, pharmacological, clinical, and genetic evidence, which indicates that the lipid bilayer has a barrier function and that specific transport activities are needed in the membrane. Consequently, the ER lumen can be regarded as a separate metabolic compartment. This article overviews the best characterized intraluminal processes in which the compartmentation is important either by defining an intraluminal milieu, by limiting the rate of the reaction, by determining the specificity, or by creating a common substrate pool because of the colocalization.
Enzymatic Synthesis of Carbohydrate‐Containing Biomolecules
Authors: Yu Hai , Chen Xi 
Published: February 2008

Abstract
As important biomolecules in living organisms, carbohydrates have received increasing attention in recent years. Their important roles in biologic events are being continuously unraveled. The development of synthetic methodologies, including both chemical and enzymatic methods, contributes greatly to the advance of the field of glycoscience. The involvement of regio‐ and stereo‐selective enzymes in the synthesis of complex carbohydrate‐containing molecules has become an indispensable approach. Many enzymes involved in the biosynthesis and biodegradation of carbohydrates have been characterized and have been applied for the production of carbohydrate‐containing biomolecules, including oligosaccharides, polysaccharides, glycoproteins, glycolipids, and glycosylated natural products. A range of strategies for enzymatic synthesis have also been developed, such as protein engineering of glycosidases and glycosyltransferases by site‐directed mutagenesis or directed evolution, one‐pot multiple‐enzyme synthesis, sugar nucleotide regeneration, solid‐phase enzymatic synthesis, synthesis using immobilized enzymes, and cell‐based synthesis. Enzymatic synthesis will continue to play critical roles in obtaining complex carbohydrate‐containing biomolecules. Future efforts should focus on identifying synthetically useful enzymes such as those with flexible or novel substrate specificity and those that can form new bonds. This identification can be achieved by functional genomics and mutagenesis studies. Development of novel enzymatic synthetic methods is also critical to access diverse naturally occurring and non‐natural derivatives of carbohydrates and glycoconjugates.
Fluorescence Spectroscopy: Applications in Chemical Biology
Authors: Sapsford Kim E. , Berti Lorenzo , Medintz Igor L. 
Published: February 2008

AbstractFluorescence spectroscopy in all of its variations can be considered among the most powerful types of analysis available to chemical biology. However, to be useful almost all applications are dependent on optimal labeling of biomolecules with a fluorophore and on the appropriate choice of analytical technique. In this article, we examine the applications and contributions of fluorescent spectroscopy to chemical biology in three inter‐related sections. We first examine the properties of the common fluorophores available from many disparate structural and functional classes, which includes a discussion of their individual benefits and liabilities in the context of their application. The available conjugation chemistries used to attach fluorophores to myriad biomolecules are next reviewed. As each class of biomolecule differs in both structure and function, the focus here is on strategies for the specific labeling of different functional groups. Last, some major types of fluorescent spectroscopy and the associated biologic questions and analysis that can be addressed with them are covered briefly.
Fluorescence Techniques for Proteins
Authors: Johnson Carey K. 
Published: February 2008

AbstractBiologists and chemists are increasingly turning to fluorescence to investigate proteins. Not only is fluorescence detection highly sensitive, but it can also report specific information about a range of properties of proteins. For example, fluorescence can be used to probe the environment of fluorescent molecules, interactions with other proteins, and the motions of proteins over time scales from picoseconds to seconds. This article surveys the properties of biologic fluorophores that can be used to study proteins and introduces the fluorescence techniques commonly applied to proteins, with an emphasis on the information generated. Techniques discussed include steady‐state emission, time‐resolved detection, fluorescence anisotropy or depolarization, energy transfer, fluorescence correlation spectroscopy, single‐molecule spectroscopy, and fluorescence imaging.
Hemes in Biology
Authors: Ortiz de Montellano Paul R. 
Published: February 2008

AbstractHeme (iron protoporphyrin IX) is a fundamental factor in biology with many physiologic roles. Its biosynthesis and degradation are regulated tightly because heme in excess of that required for incorporation into the available apoproteins is toxic. Heme itself is the dominant form in biology, but it is modified additionally to satisfy specific biochemical requirements. Both the biosynthesis of heme and its distribution into the various compartments of the cell and organism require the intervention of heme transporters. In contrast to the passive transport afforded by proteins like albumin, the transfer of heme across membranes is mediated by energy‐dependent transporters. One role of heme is to function as a regulatory molecule whose concentration controls the translational expression of multiple genes directly. As the prosthetic group of receptors that respond to oxygen, nitric oxide (NO), and other iron ligands, it is also involved in signaling. Finally, it is the prosthetic group of diverse families of hemoproteins, including the globins, cytochromes, P450 monooxygenases, NO synthases, dioxygenases, peroxidases, peroxygenases, and catalases.
Hormone Signaling
Authors: Weatherman Ross V. 
Published: February 2008

AbstractHormone signaling has always been a field that has required working at the chemistry–biology interface. The development of new chemical tools plays a major role in understanding the molecular mechanisms of hormone signaling and the physiologic outcomes of hormone receptor action. This article will outline the relevance of molecular endocrinology to the field of chemistry and the use of chemical approaches to solving problems in hormone research. The basic biologic outline of a hormone signaling system and the different classes of hormone molecules and their receptors will be discussed. In addition, several research areas in which new chemical tools have been playing key roles will be described in more detail, including the discovery of ligands for orphan hormone receptors, the development of non‐natural hormone receptor mimics, and the use of selective hormone receptor modulators to understand the role of specific hormone receptor signaling pathways. Hormone signaling systems that will be discussed include the thyronamines and trace amine receptor, the liver X and farnesol X receptors, small molecules capable of binding to peptide hormone receptors, the melanocortin receptor family, the estrogen receptor, and chemically orthogonal hormone receptor–ligand pairs. Major challenges facing the field as well as some different experimental methods used to study hormone signaling will also be discussed.
Hydration Forces
Authors: Todd Brian A. , Sidorova Nina Y. , Rau, Donald C. , Stanley Christopher 
Published: February 2008

Abstract
Force measurements on a wide variety of biologic macromolecules indicate that the perturbation of water structuring as hydrated surfaces closely approach can dominate interaction energetics. Forces with remarkably similar characteristics are observed for the repulsive interactions of charged polymer surfaces, of uncharged polymer surfaces, of charged solutes with uncharged surfaces, and of uncharged solutes with charged surfaces stressing the universality of the hydration force in aqueous solution. Repulsive interactions are caused by a disruption of the hydrogen bonding network of the intervening water between surfaces. The available measurements of forces between macromolecules that spontaneously assemble are consistent with an attractive hydration interaction. A water‐order parameter theory has been developed that is successful for predicting force curve behaviors. The direct involvement of water structuring in the interaction between macromolecules has important consequences for recognition, assembly, and conformational transitions that underlie biologic function.
Inorganic Chemistry in Biology
Authors: Bertini Ivano , Turano Paola 
Published: February 2008

AbstractSeveral inorganic chemical elements play fundamental roles in biological processes. The contribution of inorganic chemistry to the understanding of biological processes is presented here from a historical perspective: from the first discoveries of metal ions in living organisms to the modern approaches of inorganic structural biology and bioinformatics, through the characterization of metal binding sites in proteins and in biomimetic model compounds. Definitions are provided for the fundamental concepts of metal cofactor, metalloprotein, and metalloenzyme.
Ion Channels in Medicine
Authors: Lehmann‐Horn Frank , Jurkat‐Rott Karin 
Published: February 2008

Abstract
Our current understanding of ion channels has been made possible by techniques such as electrophysiology and molecular biology, but genetics‐based approaches inspired by associated diseases have pointed to regions of functional significance on the ion channels. The ion channelopathies are caused by mutations of corresponding genes or autoantibodies. Although the channels form a highly diverse group (cation, anion, voltage‐gated, ligand‐gated) and are expressed in excitable and nonexcitable tissues, underlying mutations show recurrent patterns within functionally essential protein parts and lead to common clinical features and almost predictable mechanisms of pathogenesis. This knowledge will prove useful for development of treatment strategies for individuals with various genetic backgrounds and will contribute to both the effectiveness and safety of drugs in the future.
Iron‐Sulfur World
Authors: Wächtershäuser Günter 
Published: February 2008

AbstractThe theory of a chemo‐autotrophic origin of life in an Iron‐Sulfur World postulates quenched, aqueous flows of volcanic exhalations as sites for the emergence of the pioneer organism of life, which are characterized by a composite structure with an inorganic substructure and an organic superstructure. Iron, nickel, and other transition metal centers in the substructure are catalytic for the reductive formation of low‐molecular‐weight organic compounds by carbon fixation from volcanically derived carbonyl, cyano, sulfido, ammino, and other ligands. Some organic products become transition metal ligands instatu nascendiwith the effect of ligand‐accelerated autocatalysis as a chemical basis of pioneer reproduction, inheritance, and evolution. This unitary structure‐function relationship of the pioneer organism constitutes the “Anlage” for two major parallel strands of evolution, genetization, and cellularization, and the “mystery” of an increase of complexity throughout evolution is simply caused by the primal synthetic drive of the autotrophic pioneer organism that may well be persisting to this day.
Isoprostanes
Authors: Milne Ginger L. , Morrow Jason D. 
Published: February 2008

AbstractThe isoprostanes are a unique series of prostaglandin‐like compounds formedin vivovia a nonenzymatic mechanism involving the free radical‐initiated peroxidation of arachidonic acid. This article summarizes our current knowledge of these compounds. Herein, a historical account of their discovery and the mechanism of their formation are described. Methods by which these compounds can be analyzed and quantified are also discussed, and the use of these molecules as biomarkers ofin vivooxidant stress is summarized. In addition to being accurate indices of lipid peroxidation, some isoprostanes possess potent biological activity. This activity will be discussed in detail. Finally, in more recent years, isoprostane‐like compounds have been shown to be formed from polyunsaturated fatty acids, including eicosapentaenoic acid and docosahexaenoic acid. These findings will be summarized as well.
Kinases and Dephosphorylases: Chemistry and Roles
Authors: M. Ulrich Scott 
Published: February 2008

AbstractProtein kinases and protein phosphatases catalyze phosphorylation and dephosphorylation of cellular proteins. Posttranslational protein phosphorylation is a major mechanism of signal transduction in eukaryotes; it serves as a reversible switch that alters the activity of target proteins as a means to link stimuli to the appropriate cellular response. In this article, I will review the structures and mechanisms of protein kinases and phosphatases as well as describe chemical tools developed to study protein phosphorylation.
Lantibiotics: Biosynthesis and Modes of Action
Authors: Furgerson‐Ihnken L.A. , van der Donk Wilfred A. 
Published: February 2008

AbstractLantibiotics are a unique class of antimicrobial peptides produced by Gram‐positive bacteria. They are synthesized ribosomally as precursor peptides and undergo extensive posttranslational modification to attain their biologically active structures. These modifications include dehydration of serine and threonine residues that produce dehydroalanines and dehydrobutyrines, followed by intramolecular addition of cysteine thiols to the unsaturated amino acids. The lantibiotic biosynthetic machinery displays low substrate specificity bothin vivoandin vitro, which allows for the engineering of novel lantibiotics. The polycyclic peptides exert their biological activity through several modes of action including the sequestration of the cell wall precursor lipid II and pore formation in bacterial membranes. Because of their high potency, several commercial applications of lantibiotics are being developed.