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Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy. antibiotics | flux balance analysis | virtual screening doi/10.1073/pnas.0909181107

Thirty years of pursuit have failed to yield a drug to take on one of the deadliest families of cancer-causing proteins. Now some researchers are taking another shot. When Stephen [...]

In 1537, the Swiss German scientist Paracelsus conceived a method for creating a miniature person who 'will look somewhat like a man, but transparent, without a body'. However, his protocol [...]

Premarketing studies of drugs, although large enough to demonstrate efficacy and detect common adverse events, cannot reliably detect an increased incidence of rare adverse events or events with significant latency. For most drugs, only about 500 to 3000 participants are studied, for relatively short durations, before a drug is marketed. Systems for assessment of postmarketing adverse events include spontaneous reports, computerized claims or medical record databases, and formal postmarketing studies. We briefly review the strengths and limitations of each. Postmarketing surveillance is essential for developing a full understanding of the balance between benefits and adverse effects. More work is needed in analysis of data from spontaneous reports of adverse effects and automated databases, design of ad hoc studies, and design of economically feasible large randomized studies.

Byline: Harish. Kumar, Ajay. Prakash, Phulen. Sarma, Bikash. Medhi Since long, two dimensional printing technologies (flexographic printing and inkjet technology) are being applied in the pharmaceutical sector and inclusion of [...]

Considerable progress in the pharmacotherapy of epilepsy has been witnessed during the 20th century. However, despite the development of various antiepileptic drugs, about a third of patients are resistant to current pharmacotherapies. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not affect the progression or underlying natural history of the condition. Furthermore, currently there are no drugs available that prevent the development of epilepsy following, for example, head trauma. The rapid expansion of information about the cellular, molecular and genetic mechanisms of epilepsy is expected to lead to more effective therapies, prevention or even a cure for different types of epilepsy. In this article, I assess the current status of antiepileptic therapies and highlight innovative approaches for future treatments.

Genetically encoded libraries of peptides and oligonucleotides are well suited for the identification of ligands for many macromolecules. A major drawback of these techniques is that the resultant ligands are subject to degradation by naturally occurring enzymes. Here, a method is described that uses a biologically encoded library for the identification of D-peptide ligands, which should be resistant to proteolytic degradation. In this approach, a protein is synthesized in the D-amino acid configuration and used to select peptides from a phage display library expressing random L-amino acid peptides. For reasons of symmetry, the mirror images of these phage-displayed peptides interact with the target protein of the natural handedness. The value of this approach was demonstrated by the identification of a cyclic D-peptide that interacts with the Src homology 3 domain of c-Src. Nuclear magnetic resonance studies indicate that the binding site for this D-peptide partially overlaps the site for the physiological ligands of this domain., For the purposes of drug discovery, there are potential advantages in the use of genetically encoded libraries, such as phage display (1, 2), 'peptide on plasmid' (3), and in vitro [...]

Pharmacological modulations, rendering an increase in intracellular concentrations of ceramide and resulting in a ceramide-associated signaling phenomenon, stimulate DNA disintegration and cell death through a sphingomyelin pathway. Multiple biochemical techniques using human leukemic cell lines, HL-60 and U937, and murine fibrosarcoma cell lines, L929/LM and WEHI 164/13, facilitate the analysis of the role of ceramide-associated signaling during tumor necrosis factor alpha-stimulated apoptosis. Agarose gel electrophoresis resolved oligonucleosomal fractions, derived from cell lines treated with TNF-alpha, reflect apoptosis-specific patterns.

Peptide ligands for concanavalin A (Con A), a sugar-binding protein, were isolated. The procedure involved screening a large and diverse epitope library expressed on filamentous phage. Characterization of the peptides showed that they could bind competitively with Con A's normal carbohydrate ligand. This indicates that the peptide ligands bind at or near the sugar-binding site. Although peptides themselves serve as poor drug candidartes, they may be used to provide chemical information to develop more pharmacologically active agents.

The emergence of innovative research methodologies has influenced the direction of pharmaceutical research and drug development in Germany. These innovations promise faster and safer drug development. Moreover, they have enabled the pharmaceutical industry to downscale its research materials and methodologies to come up with drugs that are more cost effective and target specific. The direction of pharmacology will depend on the utilization and optimization of these innovations.

Combinatorial chemistry is a hot field, and if interest from company job scouts is any gauge, it's only getting hotter. It burst on the scene in the early 1990s as [...]

A technological explosion is on the horizon that will revolutionize the testing platforms available for molecular diagnostics. Soon, the instrumentation and technology will be made available to quantitate pathogens rapidly and precisely, detect genetic mutations or polymorphisms and provide answers to questions relating to pathogenesis, host immunity and drug resistance.

A new class of contrast agents for magnetic resonance imaging (MRI) has emerged that is sensitive to biochemical activity. Enzyme-activated agents offer the possibility of mapping gene expression in living animals, whereas pH-sensitive agents are of particular interest for detection of abnormal tissue. Contrast agents selective for calcium, an important second messenger, can provide information about signal transduction events. Other efforts in contrast agent development are directed toward improving delivery by conjugating contrast agents to moieties that target certain tissues or that facilitate uptake. The development of new agents introduces a means for using MRI to probe biochemical activity in living organisms.