Current Drug Discovery Technologies - Volume 13, Issue 3, 2016

Costus speciosus is native to South East Asia, especially found in India, Srilanka, Indonesia and Malaysia. C. speciosus have numerous therapeutic potentials against a wide variety of complains. The therapeutic properties of C. speciosus are attributed to the presence of various ingredients such as alkaloids, flavonoids, glycosides, phenols, saponins, sterols and sesquiterpenes. This review presented the past, present, and the future status of C. speciosus active ingredients to propose a future use as a potential anticancer agent. All possible up-regulation of cellular apoptotic molecules as p53, p21, p27, caspases, reactive oxygen species (ROS) generation and others attribute to the anticancer activity of C. speciosus along the down-regulation of anti-apoptotic agents such as Akt, Bcl2, NFKB, STAT3, JAK, MMPs, actin, surviving and vimentin. Eventually, we recommend further investigation of different C. speciosus extracts, using some active ingredients and evaluate the anticancer effect of these chemicals against different cancers.

The scintillation proximity assay (SPA) technology has been widely used to establish high throughput screens (HTS) for a range of targets in the pharmaceutical industry. PDE12 (aka. 2'- phosphodiesterase) has been published to participate in the degradation of oligoadenylates that are involved in the establishment of an antiviral state via the activation of ribonuclease L (RNAse-L). Degradation of oligoadenylates by PDE12 terminates these antiviral activities, leading to decreased resistance of cells for a variety of viral pathogens. Therefore inhibitors of PDE12 are discussed as antiviral therapy. Here we describe the use of the yttrium silicate SPA bead technology to assess inhibitory activity of compounds against PDE12 in a homogeneous, robust HTS feasible assay using tritiated adenosine-P-adenylate ([3H]ApA) as substrate. We found that the used [3H]ApA educt, was not able to bind to SPA beads, whereas the product [3H]AMP, as known before, was able to bind to SPA beads. This enables the measurement of PDE12 activity on [3H]ApA as a substrate using a wallac microbeta counter. This method describes a robust and high throughput capable format in terms of specificity, commonly used compound solvents, ease of detection and assay matrices. The method could facilitate the search for PDE12 inhibitors as antiviral compounds.

Hyperglycaemia in diabetic patients causes diverse range of complications and the earliest among them is diabetic cataract. The role of aldose reductase, the key enzyme in polyol pathway, is well known in the genesis of cataract in chronic diabetic patients. Controlling of sorbitol flux into lens epithelial cells through aldose reductase inhibitors is an important treatment strategy. Due to the side effects of many drugs so far developed, the development of aldose reductase inhibitors from natural sources has gained considerable attention. This study was undertaken to identify suitable drugs for diabetic cataract using molecular modeling and simulation methods. A series of 18 luteolin derivatives having in vitro inhibitory potential against aldose reductase was used to develop a common pharmacophore hypothesis AHRRR and atom-based 3D-QSAR model. The model was used for virtual screening of ZINC database and the resultant hits were docked against aldose reductase. The two drug candidates which belonged to benzazepine class of drugs scored high in the molecular docking. They were further examined for their activity and pharmacokinetic behaviour. Their druglikeness behaviour was found suitable to be used as drugs as per Lipinski's rule of five criteria. Human intestinal absorption (HIA), skin permeability (SP), blood brain barrier (BBB) penetration and plasma protein binding (PPB) was found to be in the acceptable range. Based on the results, these drugs could be considered as potential candidates in further drug development against diabetic cataract.

The study’s background and aim: In this investigation, the safety property of M2000 (β-D-mannuronic acid) on differentiation, maturation and function of dendritic cells, was determined. β-D-mannuronic acid, as a novel immunosuppressive and anti-inflammatory agent, has been tested in various experimental models. In addition, DC-based immunosuppressive drugs can suppress the progression of autoimmune diseases, although, their notable side effects in increasing the risk of infectious diseases and cancers should be considered. Materials and Methods: The effect of M2000 on differentiation, maturation and function of dendritic cells was examined. To investigate how M2000 affects human dendritic cells (DC) in a defined inflammatory environment, human peripheral blood mononuclear cells (PBMC) were isolated from healthy blood and monocytes were purified using anti-CD14 microbeads. Monocytes were incubated with M2000 in two different doses (6 and 12 J.g/well) along with adding the granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 for inducing monocytes to immature DC and lipopolysaccharide for running DC maturation. The differentiation, maturation and function of dendritic cells were examined with flow cytometry and ELISA method. Result: The results demonstrate that M2000 has no significant side on differentiation, maturation and function of dendritic cells in immature DC and mature DC process in vitro. Conclusion: Our findings show that β-D-mannuronic acid (m2000) as a safe agent had no adverse effect on differentiation, maturation and function of dendritic cells which might be recommended as a novel immunosuppressive agent with no or fewer side effects in increasing the risk of infectious diseases and cancers.

With reference to challenges in developing varied and exceedingly complex scaffolds expeditiously through atom economy, domino reactions have assumed a significant role in several transformative endeavors towards established pharmaceuticals and new chemical entities across diverse therapeutic classes such as HIV integrase inhibitors, DPP4 [dipeptidyl peptidase IV] inhibitors, GSK- 3 (Glycogen Synthase Kinase 3) inhibitors, neoplastic drugs and microtubule antagonists. The very large chemical space of Domino Reactions can be leveraged for the design strategy of drugs and drug- like candidates with leading examples like Indinavir (Crixivan), Trandolapril (Mavik), Biyouyanagin A, endo pyrrolizidinone diastereomer [GSK] and several others. Domino reactions therefore constitute an integral part of both creative and functional aspects of drug design and discovery, contributing both enhanced efficiency as well as synthetic versatility to pharmaceutical drug design.