Current Medicinal Chemistry - Volume 14, Issue 4, 2007

The role of cell adhesion molecules (CAMs), such as intercellular cell adhesion molecule-1 (ICAM- 1), vascular endothelial cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin, has been studied extensively in the process of inflammation. These molecules are responsible for recruiting leukocytes onto the vascular endothelium before extravasation to the injured tissues. Some circulating cancer cells have been shown to extravasate to a secondary site using a process similar to inflammatory cells. The most studied ligands for CAMs expressed on cancer cells, sialyl Lewis (a/x) antigens, are shown to be involved in adhesion to endothelial cells by binding to E-selectin. This process, shared by inflammatory cells and cancer cells, may partially explain the link between inflammation and tumorigenesis. Furthermore, this process may elucidate the therapeutic benefit of anti-inflammatory drugs in cancer treatment. The complexity of the tumor microenvironment has been revealed in the past decade. Currently, intense investigation is aimed at various aspects of the tumor microenvironment in addition to the tumor cells themselves. Here, we review the role of CAMs in extravasation of circulating cancer cells, a key step in metastasis.

Melanoma is the most aggressive form of skin cancer and advantages stages are inevitably resistant to conventional therapeutic agents. In particular, the inability of undergo apoptosis in response to chemotherapy and other external stimuli poses a selective advantage for tumor progression, metastasis formation as well as resistance to therapy in melanoma. Herein, we will review the discovery of MDR transporters and the apoptotic mechanisms used by melanoma cells. Furthermore, the novel strategies to overcome tumor chemoresistance will also discuss. In particular, we will review the cancer stem cell hypothesis and how the failure of MDR reversal agents might increase the therapeutic index of substrate antineoplastic agents.

Hydrophobic interactions play a key role in the folding and maintenance of the 3-dimensional structure of proteins, as well as in the binding of ligands (e.g. drugs) to protein targets. Therefore, quantitative assessment of spatial hydrophobic (lipophilic) properties of these molecules is indispensable for the development of efficient computational methods in drug design. One possible solution to the problem lies in application of a concept of the 3-dimensional molecular hydrophobicity potential (MHP). The formalism of MHP utilizes a set of atomic physicochemical parameters evaluated from octanol-water partition coefficients (log P) of numerous chemical compounds. It permits detailed assessment of the hydrophobic and/or hydrophilic properties of various parts of molecules and may be useful in analysis of protein-protein and protein-ligand interactions. This review surveys recent applications of MHP-based techniques to a number of biologically relevant tasks. Among them are: (i) Detailed assessment of hydrophobic/hydrophilic organization of proteins; (ii) Application of this data to the modeling of structure, dynamics, and function of globular and membrane proteins, membrane-active peptides, etc. (iii) Employment of the MHP-based criteria in docking simulations for ligands binding to receptors. It is demonstrated that the application of the MHP-based techniques in combination with other molecular modeling tools (e.g. Monte Carlo and molecular dynamics simulations, docking, etc.) permits significant improvement to the standard computational approaches, provides additional important insights into the intimate molecular mechanisms driving protein assembling in water and in biological membranes, and helps in the computer-aided drug discovery process.

Over the last decade, much research has focused on the potential health benefits of antioxidants and indeed many synthetic and natural compounds have been evaluated for their antioxidant profile. However, in several studies only a limited number of assays, often poorly validated, are used and the techniques available frequently lack specificity. These limitations may incorrectly influence the results. This review will therefore focus on several pitfalls that may emerge in vitro and in vivo antioxidant research. First, different in vitro techniques to determine antioxidant potential are discussed, including radical scavenging assays and fingerprinting methods. As a rule, a panel of different assays is indispensable to characterize and establish in vitro antioxidant activity. Furthermore, as problems of absorption, distribution, metabolism and excretion are only accounted for by in vivo studies, the need for in vivo antioxidant research is pointed out. Several methods to characterize the in vivo activity of antioxidants, including major drawbacks and pitfalls of some assays, have been discussed. The availability of both a representative “oxidative stress” animal model and a battery of well-validated assays to assess the broad diversity of oxidative damage and antioxidative defence parameters, are crucial for antioxidant research in vivo.

A large number of molecules in the immune system are encoded by multigene families. These genes are rich in pairs of activating and inhibitory receptors that share the same ligands, thereby playing a crucial role in immunoregulation. Furthermore, multigene families tend to be highly polymorphic. Thus, multigene families are strong candidates for containing genes that enhance susceptibility to immune system-related diseases. Here, we review studies from our group, as well as other investigators, on three multigene families that belong to the immunoglobulin (Ig) - like receptor superfamily: Fcγ receptor (FCGR), killer cell Ig-like receptor (KIR) and leukocyte Ig-like receptor (LILR) families. FCGR genes have been implicated in susceptibility to systemic lupus erythematosus (SLE). In FCGR2B encoding an inhibitory receptor expressed in B cells, monocytes and dendritic cells, a polymorphism within the transmembrane region, Ile232Thr, was identified and found to be associated with susceptibility to SLE in three Asian populations. Functional analyses revealed that SLE-associated FcγRIIb-232Thr was less efficient in entering the membrane lipid raft, and exhibited reduced inhibitory potential against B cell receptor signaling. Although the frequency of this polymorphism was low in Caucasians, another polymorphism within the promoter region was reported to be associated with SLE. KIR/HLA combinations have been shown to be associated with various autoimmune and infectious diseases. Recently, LILR families have also been found to be highly polymorphic, and association with several diseases has been identified. These results emphasize the role of multigene families in the diversity of human immune response and susceptibility to diseases.

The development of a new therapeutic drug is a complex, lengthy and expensive process. On average, only one out of 10,000 - 30,000 originally synthesized compounds will clear all the hurdles on the way to becoming a commercially available drug. The process of early and full preclinical discovery and clinical development for a new drug can take twelve to fifteen years to complete, and cost approximately 800 million dollars. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of this time and money consuming process. Here we reviewed the application of the EIIP/ISM bioinformatics concept for the development of new drugs. This approach, connecting the electronion interaction potential of organic molecules and their biological properties, can significantly reduce development time through (i) identification of promising lead compounds that have some activity against a disease by fast virtual screening of the large molecular libraries, (ii) refinement of selected lead compounds in order to increase their biological activity, and (iii) identification of domains of proteins and nucleotide sequences representing potential targets for therapy. Special attention is paid in this review to the application of the EIIP/ISM bioinformatics platform along with other experimental techniques (screening of a phage displayed peptide libraries, testing selected peptides and small molecules for antiviral activity in vitro) in development of HIV entry inhibitors, representing a new generation of the AIDS drugs.

Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin (BH4) dependent enzymes, i.e. the aromatic amino acid hydroxylases (AAHs). The reactions catalyzed by these enzymes are important for biomedicine and their mutant forms in humans are associated with phenylketonuria (phenylalanine hydroxylase), Parkinson's disease and DOPA-responsive dystonia (tyrosine hydroxylase), and possibly neuropsychiatric and gastrointestinal disorders (tryptophan hydroxylase 1 and 2). We attempt to rationalize current knowledge about substrate and inhibitor specificity based on the three-dimensional structures of the enzymes and their complexes with substrates, cofactors and inhibitors. In addition, further insights on the selectivity and affinity determinants for ligand binding in the AAHs were obtained from molecular interaction field (MIF) analysis. We applied this computational structural approach to a rational analysis of structural differences at the active sites of the enzymes, a strategy that can help in the design of novel selective ligands for each AAH.

The essential nature of many metals is counterbalanced by the toxic effect that they can exert on both the eukaryotic and prokaryotic cell when not properly controlled. As such, virtually all organisms have developed regulatory systems that are required to maintain metal ion homeostasis. Helicobacter pylori is arguably the most successful bacterial pathogen in the world; the bacterium colonizes more than 50% of the world's population. H. pylori lives in the acidic environment of the stomach and causes a persistent infection that results in disease sequelae such as gastritis, iron-deficiency anemia, ulcer disease and gastric cancer. A requirement of colonization is that the bacterium successfully competes with host cells for available metal ions. As such, it is perhaps no surprise that several crucial colonization factors utilize metal as an essential cofactor. Recent investigations into the absolute requirement for different metal ions and the need to manage their use have shown that metal ion homeostasis is achieved by H. pylori through the utilization of an intricate regulatory cascade that ensures metal uptake without toxic side effects. Herein we discuss this cascade, the role that individual metal ions play in H. pylori colonization and disease and the possibility that these metal homeostasis cascade components may serve as good targets for rational drug design to eradicate H. pylori infection.

β-Carboline alkaloids are a large group of natural and synthetic indole alkaloids with different degrees of aromaticity, some of which are widely distributed in nature, including various plants, foodstuffs, marine creatures, insects, mammalians as well as human tissues and body fluids. These compounds are of great interest due to their diverse biological activities. Particularly, these compounds have been shown to intercalate into DNA, to inhibit CDK, Topisomerase, and monoamine oxidase, and to interact with benzodiazepine receptors and 5-hydroxy serotonin receptors. Furthermore, these chemicals also demonstrated a broad spectrum of pharmacological properties including sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic as well as antimicrobial activities. In this review, we summerized the biochemical and pharmacological functions of β-carboline alkaloids.

In our review by Tettamanti, et al. in Current Medicinal Chemistry, 2006, 13, 2737-2750, it has been brought to our attention that statements regarding the chromosomal localizations of chemokines were excessively generalized. Most CXC chemokines are localized to human 4q21, or 4q12-q13, curiously the widespread chemokine CXCL12 (SDF) is an exception being localized to 10q11.2. Many CC chemokines are localized to human chromosome 17q11-q12. Interestingly, a number of CXC chemokine receptors are localized to human chromosome 2 while several CC chemokine receptors are found on chromosome 3.