oa Editorial (Thematic Issue: New Advances of Drug Design in Cancer Disease Part I)

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.