Letters in Drug Design & Discovery - Volume 7, Issue 5, 2010

Various formulations containing titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl] titanium (IV) dichloride) were prepared and tested in vitro on CAKI-1 cells in order to compare the cytotoxic behaviour of the compound with different formulation reagents. Formulations were prepared with non-ionic surfactants like Cremophor EL and Tween 80, pegylated reagents PEG-400 and Solutol HS 15, and the co-solvent Soluphor P (pyrrolidone-2). All formulations were tested with and without the presence of dimethylsulfoxide. When the lipophilic derivative titanocene Y was formulated with Soluphor P and tested in vitro, an IC50 value of 10 (+/- 1) μM was observed, which is a 3-fold increase in cytotoxicity when compared to the DMSO formulation. In order to compare to a more hydrophilic titanocene this Soluphor P formulation method was extended to the water-soluble titanocene G, which is a dihydrochloride derivative of bis-[(1-methyl- 3-dimethylaminomethylindol-2-yl)cyclopentadienyl] titanium (IV) dichloride). When titanocene G was tested in vitro in the presence of Soluphor P, it resulted in a 10-fold increase in cytotoxicity with an IC50 value of 0.71 (+/- 0.24) ?μM against CAKI-1 cells.

There is still an urgent need to develop nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) with a high-genetic barrier to resistance that facilitate patient adherence and allow durable suppression of HIV-1 replication. In this study, we describe the synthesis of a novel series of N-aminoimidazole (NAIM) analogs. Each of the NAIM analogs display potent activity against wild-type recombinant purified HIV-1 RT as well as RTs containing the K103N or Y181C resistance mutations. The analogs, however, do not exhibit significant antiviral activity in cell culture and were, in general, cytotoxic. Nevertheless, these data suggest that the NAIM backbone may provide a suitable scaffold from which inhibitors active against NNRTI-resistant HIV-1 could be developed.

Acidic mammalian chitinase (AMCase) is a potential target for inflammatory disorders, including Th2-driven diseases such as asthma, allergy, atopic dermatitis and allergic rhinitis. AMCase, along with human chitotriosidase (HCHT) are the two human chitinases that are enzymatically active. In this study, a comparative analysis of AMCase (PDB id. 3FY1) was done with that of HCHT (PDB id.1WAW) and Aspergillus fumigatus chitinase (PDB id.1W9U) to identify differences in the binding site topology and interacting residues. Argadin, a natural inhibitor of chitinases, was docked into the active site of AMCase. All the proteins have the DXDXE motif, like other family 18 chitinases. There is a crucial difference in the stacking interactions in chitinases. The chitinase of Aspergillus fumigatus (AfchiB1) is unique in having Phe251 compared to Trp in others at the same position. Arg269 forms strong hydrogen bonds with argadin in HCHT and AfchiB1 but not in AMCase. Many crucial differences between the binding sites of AMCase and HCHT were identified. As AMCase has aroused considerable interest as the major target for the discovery of anti-asthma agents, these differences at the binding site of AMCase may be exploited for selective inhibitor design. The binding affinities, determined based on energy minimization studies, suggest a lower affinity of argadin for AMCase when compared to that for HCHT and AfchiB1.

HSV infection has high incidence rate and high prevalence. HSV-1 may cause cold sores, fever blisters, and encephalitis. Moreover, HSV-1 has the ability to cause the latent infection of neurons. Therefore, the QSAR studies of HSV-1 inhibitors and drug design based on QSAR have great importance. This paper focused on the pyrazolo[1,5- a]pyridines, which are not acyclic nucleoside analog. The reported pyrazolopyridines showed potent and selective inhibition activity. In order to find novel compounds with higher activity and to develop better predictive models, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram quantitative structure activity relationship (HQSAR) methods were performed on a series of HSV-1 inhibitors. The models built by CoMFA, CoMSIA, and HQSAR were found to be suitable for the compounds investigated with good predictive power (CoMFA q2=0.669, R2=0.953; CoMSIA q2=0.693, R2=0.919; HQSAR q2=0.619, R2=0.921). 3D contour maps obtained from PLS models of CoMFA and CoMSIA, and the atom contribution map from PLS model of HQSAR indicated that small steric volumes and electron-withdrawing groups in the R2, R3 regions would be useful to improve the activity. Results showed that the established models of the present work would be helpful in studying the relationship between the bioactivity and the molecular structures and discovering more potent HSV-1inhibitors.

A series of tacrine based cholinesterase inhibitors was designed, synthesized and assayed for their biological activity. Among them, five compounds inhibited acetylcholinesterase in micromolar range and most of the compounds demonstrated much better selectivity for AChE than reference compound tacrine.

Objectives: This study aims at evaluating drug prescription patterns, the exposure to teratogenic drugs, the prevalence of chronic maternal diseases and the attitude towards the supplementation of folic acid in a selected high-risk population asking for a preconception counselling. Study Design: A descriptive study on 4077 cases of drug exposures carried out by an Italian Teratology Information Service, from January 2002 to October 2008. Results: The exposure to neurological drugs was the main reason for calling in women trying to get pregnant. Teratogenic drugs accounted for 40% of total prescriptions and chronic diseases, most of them neurological (70%), were highly prevalent (54%). Folic acid was dispensed to 54% of women at the time of call. In the subpopulation of women suffering from epilepsy, only 12% were given folic acid. Conclusions: The exposure to teratogenic drugs and the prevalence of chronic diseases is frequent in the population asking for a counselling and can increase the risk of a negative outcome of pregnancy. The prevalence of folic acid supplementation before conception is not yet sufficient and should be improved, especially in high- risk patients, such as epileptic women. The Teratology Information Service may support general health and provide information about preconception care thus improving the outcome of pregnancy, mainly in high-risk populations affected by chronic diseases and often treated by teratogenic drugs.

Fifteen new heterocyclic thiazolidinones have been synthesized from one-pot reactions of piperonylamine, arenealdehydes and mercaptoacetic acid. These compounds plus ten 2-aryl-3-(benzyl)-1,3-thiazolidin-4-ones which had been previously synthesized, were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Six of the series exhibited modest activity when compared to the first line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of multi-drug resistant tuberculosis.

Synthesis and analgesic activity studies of a series of L-amino acid based compounds were described. These compounds were designed as potential N-type Calcium Channel Blockers and their structures were confirmed by 1H NMR and ESI-MS spectra. Some of the compounds exhibited significant analgesic activity in Mouse Hot-Plate tests. According to the data of pharmacological experiments, we carried out preliminary structure-activity studies and the results indicated that this kind of compounds was useful for the development of new analgesic drugs.

We report the use of steroid-based compounds as probes for the active site of 17β-hydroxysteroid dehydrogenase, in particular, type 3 (17β-HSD3). Results suggest that the compounds were good inhibitors of 17β-HSD3 - a number were extremely potent with respect to the standard compounds used.

The past decades witnessed extensive efforts to study the relationships among small molecules (drugs, metabolites, or ligands) and proteins due to the scale and complexity of their physical and genetic interactions. Particularly, computationally predicting the drug-protein interactions is fundamentally important in speeding up the process of developing novel therapeutic agents. Here, we present a supervised learning method, support vector machine (SVM), to predict drugprotein interactions by introducing two machine learning ideas. Firstly, the chemical structure similarity among drugs and the genomic sequence similarity among proteins are intuitively encoded as a feature vector to represent a given drugprotein pair. Secondly, we design an automatic procedure to select a gold-standard negative dataset to deal with the training data imbalance issue, i.e., gold-standard positive data is scarce relative to large scale unlabeled data. Our SVM based predictor is validated on four classes of drug target proteins, including enzymes, ion channels, G-protein couple receptors, and nuclear receptors. We find that our method improves the existing methods regarding to true positive rate upon given false positive rate. The functional annotation analysis and database search indicate that our new predictions are worthy of future experimental validation. In addition, follow-up analysis suggests that our method can partly capture the topological features in the drug-protein interaction network. In conclusion, our new method can efficiently identify the potential drugprotein bindings and will promote the further research in drug discovery.

Aging is an inherently complex process and the manifestations occur within an organism at genetic, molecular, cellular, organ, and system levels. It is now believed that aging results from a complex interplay between multiple mechanisms including oxidative stress, mitochondrial DNA damage, membrane alterations, telomere loss, apoptosis and genetic mechanisms. All the above mentioned processes contribute towards the process of aging and may underlie the age related changes. The current understanding of aging process has given novel insights in potential anti-aging interventions. The current strategies for anti-aging interventions include anti-oxidant supplementation, hormonal treatment, caloric restriction, and genetic and cellular engineering techniques. Any given intervention to be acknowledged as anti-aging must be able to demonstrate delayed onset or pace of multiple age-related changes and pathologies and also to bring the health span closer to the life span.