Current Enzyme Inhibition - Volume 8, Issue 1, 2012

Welcome to the edition of the 8th Volume, number 1 of the Journal of Current Enzyme Inhibition. This issue includes four interesting reviews. Two of them are focused on natural products and on their role in cancer and cytotoxicity, one deals with a web based program to understand the essential structural features for a specific biological activity and the fourth presents iminoalditols targeting Carbohydrate processing enzymes. Bei et al., present an update on the effects of Anthocyans on the expression and function of enzymes involved in cancer development and progression. The authors discuss the preventive and/or therapeutic potential of anthocyans against human cancers. Anthocyans belong to a widespread group of plant constituents, displaying a variety of pharmacological properties, ability to scavenge reactive oxygen species, to affect the transcriptional activity of NF-κ B and to influence the functions of enzymes involved in DNA damage and in cancer-related signaling pathways. These effects rely on the inhibition of signaling by tyrosine kinase growth factor receptors, on the impairment of cAMP phosphodiesterase, proteasome chymotrypsin-like, ornithine decarboxylase and glyoxalase I activity. Since these compounds exhibit the ability to bind and inhibit a number of signaling kinases, Anthocyans are regarded as multi-target kinase inhibitors.....

Anthocyans (ACNs), i.e. anthocyanins and anthocyanidins, belong to a widespread group of plant constituents, collectively known as flavonoids, which occur in the western diet at relatively high concentrations. ACNs display a variety of pharmacological properties which make them potential anti-inflammatory and anti-cancer agents. In addition to their ability to scavenge reactive oxygen species, ACNs can affect the functions of enzymes involved in DNA damage and in cancer-related signaling pathways. The antiproliferative, proapoptotic and antiangiogenic effects of ACNs rely on the inhibition of signaling by tyrosine kinase growth factor receptors (EGFR/ErBs, c-Met, VEGFRs, PDGFRs) as well as on the impairment of cAMP phosphodiesterase, proteasome chymotrypsin-like, ornithine decarboxylase and glyoxalase I activity. ACNs interfere also with cancer cell invasion by lowering the expression of the urokinase-type plasminogen activator and matrix metalloproteinases. Further, these compounds have been found to affect the transcriptional activity of NF-κB by inhibiting the IκB kinase complex and histone acetyltransferases, the inhibition of NF-κB being closely linked with the downregulation of COX-2 expression. Finally, ACNs are regarded as multi-target kinase inhibitors due to their ability to bind and inhibit a number of signaling kinases, such as Raf, MEK, MAPKK4, PI3K and Fyn. This review will provide an update on the effects of ACNs on the expression and function of enzymes involved in cancer development and progression, and will discuss the preventive/therapeutic potential of these compounds against human cancers.

Three-dimensional pharmacophore hypothesis was built based on a set of known Protein tyrosine Phosphatase 1B (PTP1B) agonists using PharmaGist program to understand the essential structural features for Protein Tyrosine Phosphatase 1B (PTP1B) agonists. The various marketed or under development potential glitazones have been opted to build a pharmacophore model e.g. Pioglitazone, Rosiglitazone (BRL-49653), Rivoglitazone (CS-011), Darglitazone, Citaglitazone, Englitazone, Netoglitazone (MCC-555), Balaglitazone (DRF-2593) and Troglitazone. PharmaGist web based program is employed for pharmacophore development. Four points pharmacophore with the hydrogen bond acceptor (A), hydrophobic group (H), Spatial Features and aromatic rings (R) have been considered to develop pharmacophoric features by PharmaGist program. The best pharmacophore model having the Score 30.547, which has been opted to screen on ZincPharmer database to derive the novel potential antidiabetic ligands. The best pharmacophore having various Pharmacophore features, including General Features 6, Spatial Features 6, Aromatic 2, Hydrophobic 1, Donors 1, and Acceptors 2. The algorithm identifies the best pharmacophores by computing multiple flexible alignments between the input ligands. The multiple alignments are generated by combining pairwise alignments between one of the glitazone input ligand, which acts as pivot and the other glitazones as ligand. The resulting multiple alignments reveal spatial arrangements of consensus features shared by different subsets of input ligands. The best pharmacophore model has been derived using both pairwise and multiple alignment methods, which have been weighted in Pharmacophore Generation process. The highest-scoring pharmacophore model selected as potential pharmacophore model. Finally, 3D structure search have been performed on the “ZincPharmer Database” to identify potential compounds that have been matched with the proposed pharmacophoric features. The 3D ZincPharmer Database has been matched with 553 ligands hits. The physicochemical properties of 553 ligands hits have been calculated by PaDEL-Descriptor software, which have been filtered based on the Lipinski's rule of five criteria (i.e. MW <500, H-bond acceptor ≤ 10, H-bond donor ≤ 5, Log P ≤ 5) by to get the potential antidiabetic ligands. We have found various substituted “pyrido[3',2':4,5]thieno[3,2- d]pyrimidin-4(3H)-one” as potential antidiabetic ligands, which can be used for further development of antidiabetic agents. In the present research work, we have covered rational of Thiazolidinedione's nucleus based on Maximal Common Substructure (MCS) as well as Ligand-Based Pharmacophore.

Understanding and controlling carbohydrate processing enzymes (CPE) have been major issues and challenges for chemists, biochemists and clinical practitioners alike. One of the most powerful families of substances for probing active sites as well as allosteric interactions with CPEs are basic sugar analogues, in particular iminoalditols. This compound class presents a basic trivalent nitrogen instead of oxygen in the sugar ring as the common feature. Depending on the task, such molecules may show two faces, acting as powerful competitive inhibitors or as folding templates for the same CPE protein. When applied at sub-inhibitory concentration iminoalditols and derivatives thereof have become attractive as pharmacological chaperones for the treatment of lysosomal storage diseases. As such these structures can restore protein activity by assisting correct folding of mutant enzymes thus facilitating transportation to the lysosome and consequently substrate hydrolysis. This review surveys iminoalditol structures which have recently been investigated as potential pharmacological chaperones for the treatment of lysosomal storage diseases.

Natural products are important in pharmaceutical research, and many medicines are based on natural products. It is estimated that about 40% of all medicines and about 60% of anti-cancer agents are based on natural products. Plants, marine organisms, amphibians and soil micro-organisms produce cytotoxic compounds to protect themselves or their micro-environment against other organisms and species. It may be beneficial if such cytotoxic natural products affect target enzymes across a broad spectrum of organisms and species.