- Volume 2, Issue 1, 2005

This second volume of the book series, Frontiers in Medicinal Chemistry contains a collection of 26 updated articles on various aspects of medicinal chemistry, which have been previously published in the top medicinal chemistry journals, including “Current Medicinal Chemistry”, “Current Topics in Medicinal Chemistry” and “Current Pharmaceutical Design”. The articles are divided according to disease groups. The first section on Inf Read More

The viral enzyme, HIV integrase (MW 32 kDa), is one of the three key enzymes of the pol gene of HIV. HIV integrase is involved in the integration of HIV DNA into host chromosomal DNA. There is apparently no functional equivalent of this enzyme in human cells. Integration of HIV DNA into the host cell genome apparently occurs by a carefully defined sequence of DNA tailoring (3'-processing) and coupling (joining or integration) Read More

Macrolides are among the most clinically important antibiotics. However, many aspects of macrolide action and resistance remain obscure. In this review we summarize the current knowledge, as well as unsolved questions, regarding the principles of macrolide binding to the large ribosomal subunit and the mechanism of drug action. Two mechanisms of macrolide resistance, inducible expression of Erm methyltransferase an Read More

Thrombosis is the collective term for diseases caused by the localized accumulation of circulating blood elements within the vasculature that result in vessel occlusion. Conventional antithrombotic drugs target the coagulation pathways (e.g., heparins, warfarin, ximelagatran), platelet-dependent mechanisms (e.g., clopidogrel), or thrombi in situ (e.g., streptokinase). While marketed anticoagulants are very efficacious, they can par Read More

Due to the well known receptor-receptor interaction between adenosine A2A and dopamine D2 receptors in the basal ganglia, the discovery and development of potent and selective A2A adenosine receptor antagonists, became, in the last ten years, an attractive field of research to discovery new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease. Different compounds have been investigated Read More

Nitric oxide (NO) has been established as an important messenger molecule in various steps of brain physiology, from development to synaptic plasticity, learning and memory. However, NO has also been viewed as a major agent of neuropathology when, escaping controlled production it may directly or indirectly promote oxidative and nitrosative stress. The exact borderline between physiological, and therefore neuroprot Read More

Glutamate receptor signaling is essential to normal synaptic function in the central nervous system. The major ionotropic glutamate receptors (AMPA, Kainic, and NMDA) have different synaptic functions depending upon cellular and subcellular localization, subunit composition, and second messenger systems linked to the receptors. In this review, we examine major advances in glutamate receptor biology whose physiology Read More

Cannabinoids comprise three classes of compounds, the active components of Marijuana (Cannabis sativa), as well as endogenous and synthetic derivatives. To date, two distinct cannabinoid receptors (CB1 and CB2) have been discovered, but evidence for further receptor types has been brought forward. The potential use of cannabinoids for medicinal purposes has long been known, but the mechanisms of action of both Read More

New treatments are currently required for the common metabolic diseases obesity and type 2 diabetes. The identification of physiological and biochemical factors that underlie the metabolic disturbances observed in obesity and type 2 diabetes is a key step in developing better therapeutic outcomes. The discovery of new genes and pathways involved in the pathogenesis of these diseases is critical to this process, however i Read More

Estrogen receptor modulators are recognised as playing a central role in the regulation of many endocrine functions. In recent years, the discovery of many new members of this class of ligand together with the acquisition of detailed knowledge concerning the structure and molecular mechanism of action of this protein continues to attract widespread interest. This work details recent advances in the science of estroge Read More

The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors, a set of three receptor sub-types encoded by distinct genes, function as lipid sensors to regulate a broad range of genes in many metabolically active tissues. Synthetic PPAR agonists have exhibited therapeutic benefits in treating diabetes and cardiovascular diseases. The discovery of PPAR-specific ligands has led to significant advan Read More

Diabetes is among the largest contributors to global mortality through its long term complications. The worldwide epidemic of type 2 diabetes has been stimulating the quest for new concepts and targets for the treatment of this incurable disease. A new target is glycogen phosphorylase (GP), the main regulatory enzyme in the liver responsible for the control of blood glucose levels. One of several approaches to influence the a Read More

Obesity is an epidemic problem in the U. S. and many other industrialized nations. Historically, the drugs used for its treatment generally targeted small-molecule neurotransmitters. As research grows to decipher the underlying molecular mechanisms of energy homeostasis, it is becoming evident that the modulating effects of neuropeptides also are critical in the regulation of appetite and metabolism. The search for drugs Read More

Histone deacetylases (HDACs) are key enzymes in the regulation of gene expression. By maintaining the dynamic equilibrium of the acetylation status of highly conserved lysine residues on histones, they regulate chromatin remodelling and gene expression. A link between aberrant HDAC activity and cancer has been widely reported and HDAC inhibitors have been shown to inhibit the proliferation of human tumor cell lines Read More

The aim of cancer gene therapy is to selectively kill malignant cells at the tumour site, by exploiting traits specific to cancer cells and / or solid tumours. Strategies that take advantage of biological features common to different tumour types are particularly promising, since they have wide clinical applicability. Much attention has focused on genetic methods that complement radiotherapy, the principal treatment modality, or Read More

The development of farnesyltransferase inhibitors, a novel approach to non-cytotoxic anticancer therapy, has been an active area of research over the past decade. Compounds that have advanced to clinical trials were evolved both from substrate-based design efforts and from compound library screening hits. This review focuses on the effort at Merck to evolve inhibitors from the protein substrate of farnesyltransferase, w Read More

This review gives a brief account on the current status of enediyne biosynthesis and the prospective of applying combinatorial biosynthesis methods to the enediyne system for novel analog production. Methods for cloning enedlyne biosynthetic gene clusters are first reviewed. A unified paradigm for enediyne biosynthesis, characterized with (a) the enediyne PKS, (b) the enediyne PKS accessory enzymes, and (c) tailoring Read More

Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumor neovascularization and in angioproliferative diseases. Tumors cannot grow as a mass above few mm3 unless a new blood supply is induced. It derives that the control of the neovascularization process may affect tumor growth and may represent a novel approach to tumor thera Read More

The following review outlines the physiological outcome of VIP and VIP gene manipulations. Previously, we reviewed the various VIP receptors associated with biological functions ranging from growth regulation, sexual function, bronchodilation, vasodilation and immune interactions to neurotrophism. Recent Progress in VIP-based drug design is discussed below.

Biologically active small molecules that interact specifically with protein have tremendous values not only for the functional analysis of genes but also for the drug development. Chemical genetics / genomics-based approach has recently been developed and recognized as one of key solutions for this purpose. This review focuses on the utilization of this new research engine for the target mining and validation of angiogenesis i Read More

Results of various projects on Mexican Indian ethnobotany and some of the subsequent pharmacological and phytochemical studies are summarised focusing both on chemical-pharmacological as well as anthropological (ethnopharmacological) aspects of our research. We have identified taste and smell properties of medicinal (vs. non-medicinal) plants as important indigenous selection criteria. There exist well-d Read More

Natural killer T (NKT) cells are a subset of lymphocytes that express receptors characteristic of conventional T cells together with receptors typically found on natural killer cells. A key feature of NKT cells is the expression of a semi-invariant T cell receptor that is specific for glycolipid antigens presented by the unusual major histocompatibility complex class I-like molecule CD1d. While their precise immunological functions rema Read More

Lead identification and optimization is always a challenge to the medicinal chemists in drug discovery. Numbers of simple to complex and smaller to bigger organic compounds are prepared to meet the screening purpose of biological targets. Conventional solution phase synthetic methodologies are lacking the speed to run along with the need of medicinally interesting compounds due to their long reaction time, tedious work-up Read More

Pharmacophore discovery is one of the major elements of molecular modeling in the absence of X-ray structural data. While pharmacophores initially made their debut as a means for lead discovery, more recent refinements have brought them into the domain of lead optimization, e.g. as a means to define the molecular alignment in 3D-QSAR. In this review, the experiences of over a decade of confronting and solving the Read More

In recent years, tools for the development of new drugs have been dramatically improved. These include genomic and proteomic research, numerous biophysical methods, combinatorial chemistry and screening technologies. In addition, early ADMET studies are employed in order to significantly reduce the failure rate in the development of drug candidates. As a consequence, the lead finding, lead optimization and de Read More

Methods for the prediction of octanol / water partition coefficient, aqueous solubility and acid / base dissociation constants are described and discussed. The advantages and limitations of the different approaches are described and an indication of problem areas discussed. Available prediction software is described and listed and attempts are made to assess the likely reliability of the predictions. The concept of “drug- Read More

Cytochromes P450 (Cyt P450s) constitute the most important biotransformation enzymes involved in the biotransformation of drugs and other xenobiotics. Because drug metabolism by Cyt P450s plays such an important role in the disposition and in the pharmacological and toxicological effects of drugs, early consideration of ADME-properties is increasingly seen as essential for the discovery and the development of new Read More