Current Bioactive Compounds - Volume 10, Issue 2, 2014

This issue is aimed for anyone who is interested or works with drug design research, with particular interest in Cancer. We attempt to convey something of the fascination of working in the field of heoretical and Computational Medicinal Chemistry, which overlaps knowledge of chemistry, computation, physics, biochemistry, biology and pharmacology, with emphasis on Cancer. Today, different targets are being explored, characterizing the multifactor aspect of the Cancer disease. Structural features as well as a comprehensive insight into the selectivity and activity of novel ligands are of considerable interest. Multidisciplinary, theoretical-computational medicinal chemistry tools can be used to select potential inhibitors. Cancer is characterized by gene expression aberrations and genomic abnormalities which leads to misregulated acitivity of cell proliferation, apoptosis and angiogenesis. We start this Special Issue with a review on dietary polyphenols for prostate câncer therapy. In prostate cancer (PCa), many ligand-induced signaling cascades are active and may lead to pathogenic cells proliferation and survival resulting in persistent growth and deregulated cell-cycle progression. The signaling systems include receptor tyrosine kinase (RTK), insulin-like growth factor receptor (IFGR), androgen receptor (AR), epidermal growth factor receptor (EFGR), signal transducer and activator of transcription (STAT), AR-associated ornithine decarboxylase (ODC), -catenin, toll-like receptor (TLR), human cytochrome P450-dependnt monooxygenase 1A1 (9CYP1A1) and others. Signaling malfunctions lead to metastatic events such as tissue invasion. A variety of physiologically active natural dietary polyphenols and their analogues have potential for PCa chemotherapy. Protein kinases are enzymes that play important regulatory roles in cell biology. They are involved in cellular processes such as cytoskeletal rearrangement, cell cycle, immune response, nervous system function, apoptosis and transcription. The Marks (Microtubule Affinity Regulating Kinases) kinases are regulators of microtubules and their associated proteins (MAPs). The MARK3 is responsible for the phosphorylation of MAP binding sites catalyzing their cleavage. Overexpression of MARK3 causes disruption of the cell, leading to inappropriate overgrowth, neoplasms, cell death. This protein kinase is overexpressed in neck and head cancer and identified as a marker for cancer. In the second work, ligand-based drug design tools including scaffolds were used by the authors as similarity searches in order to identify possible active compounds. Filters related to physicochemical properties, molecular interaction fields, molecular dynamics simulations, prediction of toxicity and biological activity were also used. Phospholipases play important roles in intracellular and extracellular signaling generating bioactive lipid signaling molecules which regulate many cellular events (hallmarks of cancerous behaviors in cells, such as angiogenesis, proliferation, invasion and migration). Mammalian phospholipases are involved in membrane-linked and cytosolic soluble signaling pathways. Protein kinase ARF, C and RHO are identified as PLD activators of PLD. Phosphatidic acid (PA), product of PLD cleavage, modulates signaling molecules such as mTOR, S6K, RAF, RAC and RIPSK. A more complete view of PLD enzymes role within intracellular signaling is emerging. In the third work, a review is made of phospholipase D enzymes(s) in modulating cell signaling with implications for cancer drug development emphasizing the importance of identifying highly specific molecules to inhibit this enzyme in human signaling. Drug development has been strongly improved by adoption of computational methods, which yields faster development of lower costs new drugs. A collection of tools aid decision making at different stages of drug discovery (design/selection of novel ligands, identification of targets, improving affinity/pharmacokinetic/pharmacodynamics properties). Deregulation of the MARK3 protein kinase triggers a variety of diseases (cancer, diabetes, cardiovascular and nervous system disorders). These kinases constitute families of drugable targets. However, there is a high level of similarity between members of this family (50 to 85% of sequence identity) making more challenging the development of inhibitors. On the other hand, the inhibition of kinases shows great promise in anticancer treatment indicating lower cytotoxicity compared to chemotherapeutic agents used in therapy. In this fourth work, computational tools including structure-based virtual screening are used to select MARK-3 inhibitors in Cancer. These leads are used as templates for similarity screening of databases. Molecular interaction fields, molecular dynamics, pharmacophore modeling and ADMET studies are used for further filtering.

This review describes the potential of a variety of physiologically active natural dietary polyphenols (PPhs) and their analogues, including derivatives of flavonoids, stilbenes, lignans, curcuminoids, and tannins, for prostate cancer chemotherapy. The large number of scientific papers on PPhs published during the last decade, particularly those focused on their therapeutic potential against prostate cancer cell lines, indicates rising interest in this group of compounds. Several polyphenolic agents are currently being investigated in advanced clinical trials as prominent cancer drug candidates while hundreds of related compounds are being evaluated in early clinical and preclinical studies. The review also covers the key mechanisms of antitumor action of natural PPhs against cancer cells.

Protein kinases are enzymes that have a key regulatory role in cell biology involved in various cellular processes such as apoptosis, cell cycle, cytoskeletal rearrangement, immune response, nervous system function, and transcription. MARK3 protein kinase was identified as a marker for cancer, and proved to be overexpressed in head and neck cancer. With the aim of identifying possible active compounds able to perform interactions with the MARK3 protein binding site, active substructures known as scaffold were used in the process of similarity search. In this work, ligand-based virtual screening approaches were carried out to investigate potential novel MARK3 inhibitors. The obtained docking poses were rescored and after applying filters related to the physicochemical properties, as well as overlapping molecular interaction fields, toxicity prediction and prediction of biological activity spectra, three compounds were selected as the most promising and potential MARK3 inhibitors, with interest in head and neck cancer. Our results suggest that these molecules could be developed as novel lead compounds in anti-cancer drug design.

Phospholipases (PLC, PLD, and PLA) are essential in extracellular and intracellular signaling. This family of phosphopipid-hydrolizing enzymes can generate many bioactive lipid signaling molecules such as phosphatidic and lysophosphatidic acid, arachidonic acid, and diacylglycerol (DAG). The lipids produced from phospholipase enzyme activity regulate many cellular events considered hallmarks of cancerous behaviors in cells; including proliferation, migration, invasion, and angiogenesis. Mammalian phospholipase D enzymes have a complex intermediary role in many well characterized signal transduction pathways involving membrane-linked and cytosolic soluble signaling pathways. Regulation of this class of enzymes is complex: protein kinase C, ARF, and RHO proteins are identified as activators of PLD. The lipophilic product of PLD cleavage, phosphatidic acid (PA), acts as a second messenger in cells and has been shown to modulate many signaling molecules such as RAF, mTOR, S6K, and RAC. In the past decade, a more complete view of PLD enzymes, role within intracellular signaling has emerged. A thorough understanding of the cancer-associated signaling networks of the phospholipases and their products is beginning to emerge. Increased understanding of PLD’s role within cell growth and metabolism has facilitated its emergence as a potential target for cancer therapy. Novel, highly specific molecules are being identified and modified to potently inhibit this important enzyme in human intracellular signaling.

MARK3 (microtubule affinity regulating kinase 3) is a serine/threonine protein kinase. The protein kinases have a regulatory role in cell biology, involved in a variety of cellular processes such as apoptosis, cell cycle, cytoskeletal rearrangement, immune response, nervous system function, and transcription. Deregulation of these protein kinases triggers a variety of diseases such as cancer, diabetes, cardiovascular and nervous system disorders, which highlights this family of proteins as druggable targets. However, the development of competitive inhibitors to protein kinases is a challenging task due to the high level of similarity between members of this family, ranging from 50 to 85 % of sequence identity. The structure-based techniques were performed to design novel MARK3 inhibitors. Structure-based virtual screening experiments were performed selecting 20 compounds whose activity profiles were predicted using PASS and DEREK softwares. In addition, the top docking solutions were evaluated by molecular dynamics simulations.