Current Medicinal Chemistry - Volume 20, Issue 15, 2013

The deregulation of oncogenic signaling pathways which provide survival advantages to tumor cells is mediated by multiple cellular networks. Among them, the PI3K-Akt-mTOR axis, in particular the serine/threonine kinase Akt, is recognized as a key player. The kinase is hyperactivated due to a variety of mechanisms including loss of PTEN, mutations in the PI3K catalytic subunit, receptor tyrosine kinase and Ras activation. Indeed, inappropriate activation of the Akt kinase is a common event in human tumors and Akt appears to be a critical player in cell survival that may also account for the therapeutic resistance and the invasive phenotype of tumors. Inhibition of Akt signalling results in apoptosis and growth inhibition of tumour cells with elevated Akt activity. A functional role in drug resistance is supported by evidence that tumor cells with acquired resistance to antitumor agents may display increased Akt activation and that treatment with molecularly targeted agents can activate feed-back loops involving Akt. This serine/threonine kinase may therefore represent an amenable target for modulation of sensitivity to compounds with different molecular features due to its pleiotropic role in cell survival. Different types of Akt inhibitors [i.e., ATP mimetics and pleckstrin-homology (PH) domain binders] have been generated and some of them have reached the clinical setting. The present review focuses on the i) mechanisms implicating Akt in increased survival and invasive potential of tumor cells of different tumor types and ii) on the development of Akt inhibitors as modulators of drug resistance.

In this mini-review, we focus on different strategies to bring nanotools specifically to cancer cells. We discuss about a better targeting of tumor, combining the characteristics of tumor environment, the increase in nanoparticles life time, the biomarkers overexpressed on cancer cells and different physical methods for non invasive therapies. Here we detail the necessity of a synergy between passive and active targeting for an actual specificity of cancer cells.

In this review we discuss the role of ATP synthase as a molecular drug target for natural and synthetic antimicrobial/ antitumor peptides. We start with an introduction of the universal nature of the ATP synthase enzyme and its role as a biological nanomotor. Significant structural features required for catalytic activity and motor functions of ATP synthase are described. Relevant details regarding the presence of ATP synthase on the surface of several animal cell types, where it is associated with multiple cellular processes making it a potential drug target with respect to antimicrobial peptides and other inhibitors such as dietary polyphenols, is also reviewed. ATP synthase is known to have about twelve discrete inhibitor binding sites including peptides and other inhibitors located at the interface of α/β subunits on the F1 sector of the enzyme. Molecular interaction of peptides at the β DEELSEED site on ATP synthase is discussed with specific examples. An inhibitory effect of other natural/synthetic inhibitors on ATP is highlighted to explore the therapeutic roles played by peptides and other inhibitors. Lastly, the effect of peptides on the inhibition of the Escherichia coli model system through their action on ATP synthase is presented.

Glioblastoma multiforme (GBM) is known to be the most common and lethal malignant primary brain tumor. Despite vigorous basic and clinical studies over the past decades, the prognosis of patients with GBM has remained dismal. The fundamental problem with these malignancies occurs due to tumor cells' highly infiltrative nature, precluding a complete surgical resection, and a productive or acquired resistance to cytotoxic therapy. Recent studies demonstrated that GBMs exhibited remarkable cellular heterogeneity and hierarchy containing self-renewing glioma stem cells (GSCs). The malignant growth of GBM can be propagated and sustained by GSCs that are endowed with highly efficient clonogenic and tumor initiation capacities. GSCs can be identified with technical support and are responsible for the invasive potential and recurrence of GBMs. They share core signaling pathways with normal neural stem cells, but also display critical distinctions that provide important clues for useful therapeutic targets. Therefore, targeting GSCs becomes priorities for the development of novel therapeutic paradigms. Herein, we reviewed the existing and promising targeting therapies for GSCs which could effectively inhibit the tumor invasion, proliferation and recurrence of GBMs. Significant features of GSCs, such as invasive growth pattern, angiogenic potential, resistance to traditional therapy and differentiation, are important therapeutic targets. More promising strategies should target GSCs themselves by taking advantages of highthroughput technologies and dissecting the intrinsic molecular nature of GSCs. Novel chemical medicines targeting these GSCs may represent one of the most important directions. Hopefully, this could shed a light on the path we are going to.

The recent focus on protein-protein interaction networks has increasingly been shifted towards the disruption of protein complexes, which either are mediated by the binding of a globular domain in one protein to a short peptide stretch in another, or involve flat, large, and hydrophobic interfaces that classical small-molecule agents are not always ideally suited. Rational design of therapeutic peptides with high affinity targeting such interactions has emerged as a new and promising tool in discovery of potential drug candidates against associated diseases. The design is commonly based on bioinformatics methods or molecular modeling techniques, indirectly exploiting structure-activity relationship at the level of peptide sequence or directly deriving lead entities from protein complex architecture. Here, a newly rising subfield called computational peptidology that focuses on the use of computational and theoretical approaches to treat peptiderelated problems is comprehensively reviewed on the design and discovery of peptide agents targeting protein-protein interactions. We address a systematic discussion on several representative cases in which the computational peptidology is successfully employed to develop peptide therapeutics. Besides, some problems and pitfalls accompanied with the current use of computational methods in peptide modeling and design are also present.

Rheumatoid arthritis (RA) and other chronic inflammatory diseases are always the major therapeutic challenges. Recent research efforts provided new insights into the molecular basis of these diseases and new opportunities for developing improved anti-inflammatory drugs. The p38 mitogen-activated protein (MAP) kinase plays a central role in the regulation of the biosynthesis and release of several proinflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Hence, inhibition of the p38 MAP kinase is regarded as a promising therapeutic strategy for controlling inflammatory diseases. A diverse range of p38α MAP kinase inhibitors have been developed as potential anti-inflammatory agents, and some of them have entered the phase II clinical trials. The imidazole derivatives are known as competitive inhibitors at the ATP binding site of the p38α MAP kinase. Modifications on the imidazole scaffold have led to a large amount of potent p38α MAP kinase inhibitors. This review will summarize the developments of small molecule p38α MAP kinase inhibitors based on the imidazole core scaffolds in recent 10 years. Variations at the N1, C2, C4 and C5 positions of imidazole were introduced, and the structure-activity relationships of these imidazole inhibitors were also discussed.

Melatonin (N-acetyl-5-methoxy-tryptamine), a principal product of the pineal gland, is produced mainly during the dark phase of the circadian cycle. This hormone plays a crucial role in the regulation of circadian and seasonal changes in various aspects of physiology and neuroendocrine functions. In mammals, melatonin can influence sexual maturation and reproductive functions via activation of its receptors and binding sites in the hypothalamic-pituitarygonadal (HPG) axis. This review summarizes current knowledge of melatonin on the hypothalamus, pituitary gland, and gonads. We also review recent progress in clinical applications of melatonin or potentials of using melatonin, as a reducer of oxidative stress, to improve reproductive functions for the diseases such as women infertility.

Evidence indicates that cysteine protease falcipain-2 plays essential role in malaria parasites; therefore the potent and selective inhibitors of falcipain-2 may be therapeutically useful drugs for treatment of various forms of malaria parasite plasmodium. In order to understand the structure-activity correlation of falcipain-2 inhibitors, a set of ligand- and receptor-based 3D-QSAR models were, for the first time, developed in the present work employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) for 240 promising molecules. Based on the ligand-based alignment, an optimal 3D-QSAR model was obtained with good predictive power of Q2 = 0.501, R2 ncv = 0.890, SEE = 0.282, F = 153.522 and R2 pred = 0.768. And the contour maps intuitively suggest where to modify the molecular structures in order to improve the binding affinity. In addition, docking analysis and molecular dynamics simulation (MD) study were also carried out on the dataset with purpose of exploring the detailed binding modes of ligand in the falcipain-2 binding pocket. The combination of docking analysis and MD simulation shows that Gly83, Trp43 and Ala175 which formed several H-bonds are crucial for falcipain-2 inhibitors. The analysis of the best QSAR model reveals the structural features related to the activity, and provides an insight into molecular mechanisms of inhibition and possible modification of the molecules for better activity.