Letters in Drug Design & Discovery - Volume 12, Issue 9, 2015

The C-X-C chemokine receptor (CXCR)3 and its chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune disesases. Under the influence of interferon( IFN)γ, the IFNγ-inducible chemokines are secreted by lymphocytes, and by target cells (fibroblasts, epithelial cells, etc). In target tissues, Th1 lymphocytes are recruited; hence IFNγ is enhanced, which stimulates IFNγ-inducible chemokines (CXCL9, CXCL10, CXCL11) secretion reiterating the autoimmune process. Many studies have evaluated if blockade of CXCR3 or its chemokines have therapeutic significance in autoimmune diseases (for example in thyroid autoimmune disorders, etc). Peroxisome proliferator-activated receptor (PPAR)γ or -α agonists show a strong inhibitory effect on the expression and production of CXCR3 chemokines in vitro, in various kinds of cells, such as denditric cells, monocytes, macrophages, endothelial and vascular smooth muscle cells, intestinal cells, thyrocytes, fibroblasts, preadipocytes and mesangial cells, and in vivo in animal models. Further studies are ongoing to explore the use of new molecules that act as antagonists of CXCR3, or block CXCL10, in autoimmune disorders, and many interesting patents have been recently applied. Phase II studies have assessed the efficacy and safety of fully human, monoclonal antibodies to CXCL10, for the treatment of autoimmune disorders (for example rheumatoid arthritis, or ulcerative colitis).

This work reports the docking studies of compounds designed from the combination of substructures of three types of antihypertensives: angiotensin converting- enzyme (ACE) inhibitors, calcium channel blockers and renin inhibitors. Consequently, multi-target compounds are expected to be obtained. Indeed, a few purposes showed both docking scores and intermolecular ligand-enzyme interaction towards all three targets higher than the reference compounds Captopril (ACE inhibitor), Amlodipine (calcium channel blocker) and Aliskiren (renin inhibitor). Particularly, the proposed compound 18 (containing a phenyl group, a substituted dihydropyridine and a piperazinyl-like group as substituents at the indoline scaffold) is a promising ligand for all three enzymatic targets. These results, which were discussed in terms of ligand-enzyme interactions (especially hydrogen bonding between amino acid residues and ligands), indicate promising perspectives for synthesis and biological tests.

HDAC8-selective inhibitors not only explore the biological functions of HDAC8 but also proved to be immensely significant anticancer agents with few side effects. Of the several classifications, hydroxamic acid-based HDAC inhibitors proved that they produce therapeutic potential against cutaneous T-cell lymphomas (CTCL). By considering the skeleton of the hydrophobic pocket of HDAC8 and its catalytic site, about 52 chiral heterocyclic hydroxamic acid derivatives were designed as inhibitors using structure based drug design approach. Herein, we generated common feature pharmacophore for mapping the designed ligands. Furthermore, these ligands were subjected to docking by C DOCKER method and the binding energy was calculated. In addition, toxicity was predicted using ADMET and TOPKAT simulations. Finally, by combining the results of the above studies, compounds with good binding energy and less toxicity were considered as the best inhibitors. However, five compounds CMP 9, 25, 26, 33 and 38 successfully satisfied all the studies among the 52 compounds screened and appeared to be a promising potent inhibitors against HDAC8.

Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD) has been taken as a promising target for developing anti-malarial drugs. In this work, four quantitative models were generated to predict the bioactivity of 262 Pf G6PD inhibitors. Each molecule was represented by ADRIANA. Code descriptors. The whole dataset was divided into a training set and a test set randomly or by a Kohonen’s self-organizing map (SOM). Afterwards, the bioactivities of Pf G6PD inhibitors were predicted with Multiple Linear Regression (MLR) and Support Vector Machine (SVM) method, respectively. All the four models gave a correlation coefficient (r) over 0.82 and a RMSE under 0.18 on test set. By analyzing the descriptors in these models, it was observed that number of hydrogen bonding acceptors, ring complexity, σ atom charges, total atom charges and effective atom polarizabilitly properties are important for the bioactivity of Pf G6PD inhibitors.

Cancer remains a critical study since long period. Inspite of remarkable development in science, still suitable cure and treatment is not available. In humans, Hypoxia-inducible factor-1 (HIF-1) is available in good amount in tumors and is associated in various mechanisms such as metabolism of anaerobic energy, angiogenesis, drug resistance, cell subsistence and incursion etc. Hence, for the treatment of cancer, HIF-1 inhibition may be considered as an obvious strategy. Recent studies illustrate many advances in cancer biology and biotechnology for targeting new HIF-1 agents. Numerous heterocyclic compounds are available as anticancer agents and countless struggles have been placed to discover unique agents in the coming years, which can be considered as an important tool for the diagnosis of cancer. This review provides a vision for novel anticancer targets and highlights rationally designed drugs in clinical advancement, and also the budding molecules that can influence clinical care in the coming future. Although several anticancer treatments have been familiarized in the recent years, however, none of them stand up for a better cure and because of which a new and advanced treatment becomes obligatory.

Previous studies demonstrated that some pyrazole derivatives could be considered as potential anticancer agents. A series of 1,3,5-triaryl-1H-pyrazole derivatives were prepared by the reaction of phenylhydrazin and different chalcones. The previous classic synthesis method was developed for a simpler procedure. The cytotoxicity of these compounds was determined against three cancer cell lines (HT-29), (MCF-7), (AGS) as well as fibroblastic cell line (NIH-3T3) using MTT assay. These biological studies proved that 5f and 5l were the most potent compounds in this series. Furthermore, 5f showed a partial selectivity in cytotoxicity effect between the cancerous and normal cell lines.

The inhibition property of numerous carbazole derivatives for topoisomerase enzyme was checked by molecular docking which were designed by ChemDraw software followed by 3D optimization. Two series i.e. 2-[(4, 5-dihydro-2-substitutedphenyl)imidazol-1-ylamino]-1-(9H-carbazol-9-yl)ethanone (3a-3e) and 2-(9H-carbazol-9-yl)-N'-{[(4-substitutedphenyl) (piperazin-1-yl)]methyl}acetohydrazide (6a-6e) were found to be potent with minimum binding energy. Above mentioned compounds were synthesized by starting with carbazole and characterized by FTIR, 1H-NMR, 13C-NMR, MASS spectrometry and elemental analysis. All the synthesized compounds were evaluated for their anticancer activity by SRB assay method against Human Breast Cancer Line (MCF7). All the tested compounds showed moderate to good anticancer activity. Compound 3d and 6c exhibited highest activity toward the inhibition of cancer cell line.

The aim of this paper was to present the etiological factors responsible for temporomandibular joint dysfunction associated with psychoemotional disorders and possible drug therapy. Etiology of this disorder is multifactorial. The term “stress” was explained, together with its influence on the human body and its long-term effects. We emphasized the significance of factors that affect individual reaction to stress and patients’ personality features favoring incorrect behavioral pattern. We also presented the mechanism of adverse effect of stress on temporomandibular muscles and joints via the limbic system and gamma loop as well as the role of temporomandibular reflexive regulation mechanisms. We explained the differences in reactivity between skeletal and masticatory muscles to stress-inducing factors resulting from different embryonic origin, morphology, and biochemical reactions during muscle contraction and presented drug therapy.

A series of oxime carbamates derivatives were designed and synthesized as a part of our ongoing search for novel high potential agrochemicals. Their structures were confirmed by 1H NMR, 13C NMR and elemental analysis. The bioassays results indicated that some of the obtained compounds exhibited good insecticidal activity against Heliothis armigera and Plutella xylostella.

High-throughput screening (HTS) has achieved widespread popularity over the last two to three decades in drug discovery. Characterized by its simplicity, rapidness, low cost, and high efficiency, HTS can minimize the time span of drug discovery noticeably. Robotic technologies and analytic technologies are two central components of HTS, and significant progress of the technologies has been reported recently. In addition, microfluidics has emerged as a promising technology in HTS with eligible potential. Lastly, although automated synthesis is not generally seen as a part of HTS, there is a great desire for the development of high throughput synthesis to generate compound libraries and its integration into HTS. Herein the most recent advancements in the four above mentioned fields are reviewed.