Letters in Drug Design & Discovery

ISSN: 1570-1808

Abstracts


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Computational Studies of 1-Hydrazinophthalazine (Hydralazine) as Antineoplasic Agent. Docking Studies on Methyltransferase
Enrique Angeles, Víctor HugoVazquez-Valadez, Oscar Vazquez-Valadez, Ana Maria Velazquez-Sanchez, Alberto Ramirez, Luisa Martinez, Sandra Diaz-Barriga, Andres Romero-Rojas, Gustavo Cabrera, Rafael Lopez, Castanares and Alfonso Duenas-Gonzalez

Hydralazine is a drug used as anti-hypertensive, and recently reported to be a DNA methylation inhibitor able to demethylate and reactivate the expression of tumor suppressor genes in cancer. The aim of the present study was to explore the potential mechanism by which hydralazine inhibits DNA methylation. For this purpose, we assessed the structural and electronic properties between 1-hydrazinophthalazine (hydralazine) and a putative ligand methyltransferase.


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Classical and Hologram QSAR Studies on a Series of Tacrine Derivatives as Butyrylcholinesterase Inhibitors
M.S. Castilho, R.V.C. Guido & A.D. Andricopulo

Alzheimer's disease (AD) is a major neurodegenerative disease that affects mainly people over 65 years of age. The main therapeutic approach to AD is based on the use of acetylcholinesterase (AChE) inhibitors. Recent studies have shown that butyrylcholinesterase (BuChE) can also be considered an attractive target for the development of novel drugs for AD therapy. The design of new potent and selective BuChE inhibitors is of great importance in drug discovery. 2D quantitative structure-activity relationship studies were conducted on a series of potent inhibitors of human BuChE using classical and hologram QSAR (HQSAR) approaches. A training set of 40 compounds was employed to derive the models. Classical QSAR models showed moderate correlation (r2 = 0.836, q2 = 0.750), with no substantial predictive power for untested compounds. On the other hand, the best HQSAR model (r2 = 0.928, q2 = 0.723) was used to predict the potency of 10 test set compounds, and the predicted values were in good agreement with the experimental results, showing the potential of this model for new untested compounds.


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Recombinant Murine Polyoma Virus-like-particles Induce Protective Anti tumour Immunity
M. Brinkman, J. Walter, I. Jennes, M. Neugebauer, W. Bertling, S. Grein, M. Thies, M. Weigand, T. Beyer, M. Herrmann, C. Reiser and J. Hess

Subcutaneous vaccination of mice with chimerical polyomavirus-like-particles consisting of a VP1-ovalbumin (OVA252-270) fusion protein induced immunodominant H-2Kb-restricted and OVA257-264-specific CD8 T cells in mice. Single immunisations with VP1-OVA252-270 capsoids failed to have beneficial effects on tumour protection, only double vaccinations in weekly intervals protected mice from lethal MO5 melanoma challenge.


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Thymidine Phosphorylase Over-Expression in Oral Squamous Carcinoma Tissue as a Potential Target of Capecitabine
G. Ranieri, R. Patruno, G. Fiore, G. Saponaro, A. Paradiso and L. Grammatica

Advanced oral squamous carcinoma (OSC) is typically treated with 5- Fluorouracil (5-FU) based regimens. Capecitabine (CAP) is a thymidine phosphorylase (TP) activated oral fluoropyrimidine, rationally designed to generate 5-FU preferentially within tumours. The high activity of CAP in intestinal and breast cancer suggests that CAP may have a role in the therapy of OSC. This tumour selectively is achieved through exploitation of the significantly higher activity of TP in tumour compared with healthy tissue. In the present study, the epithelial and macrophages TP expression were significantly higher in OSC than in non-dysplastic oral leukoplakia (NDOLP) (p=0.004, p=0.005; respectively). Because OSC is sensitive to 5-FU, and TP expression is significantly higher in OSC than in NDOLP, TP-activated CAP could be a promising therapy worthy of clinical investigation.


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Szeged Index – Applications for Drug Modeling
Padmakar V. Khadikar, Sneha Karmarkar, Vijay K. Agrawal, Jyoti Singh, Anjali Shrivastava, Istvan Lukovits & Mircea V. Diudea

In this review we describe various applications of Szeged (Sz) index for modeling physicochemical properties as well as physiological activities of organic compounds acting as drugs or possess pharmacological activity.


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New Drug Design for Gene Therapy — Taking Advantage of Introns
Shi-Lung Lin and Shao-Yao Ying

A novel gene modulation system was identified within mammalian introns, regulating intracellular gene transcripts homologous to certain 5’-proximal non-snRNP-binding regions of spliced introns. This gene modulation system can be manipulated for the analysis of gene function and development of gene-specific therapeutics, using artificial introns with 5’-proximal hairpin inserts.


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Adipopharmacology, a Novel Drug Discovery Approach: A Metabotrophic Perspective
G.N. Chaldakov, M. Fiore, A.B. Tonchev & L. Aloe

“Adipopharmacology” connotes the adipotargeting studies aimed at drug discovery. Here we focus on adipopharmacology of nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor and metallothioneins. Because these factors improve glucose, lipid and antioxidant metabolism, we named them metabotrophic factors (metabotrophins).


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Hologram QSAR Studies on Farnesoid X Receptor Activators
Káthia M. Honório, Richard C. Garratt, Igor Polikarpov & Adriano D. Andricopulo

Farsenoid X receptor (FXR) is an attractive drug target due to its role in the regulation of cholesterol and bile acid levels. Hologram quantitative structure-activity relationships (HQSAR) were conducted on a series of FXR activators, and the final model obtained was used to predict the potency of 10 test set compounds. The predicted values were in good agreement with the experimental results.


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In-Vitro Searching for a New Potent Reactivator of Acetylcholinesterase Inhibited by Nerve Agent VX
K. Kuca, J. Cabal, J. Bajgar and D. Jun

Organophosphorus compounds, especially nerve agents, inhibit enzyme acetylcholinesterase (AChE; EC 3.1.1.7) in an irreversible manner. Atropine plus an oxime reactivator are used as an effective treatment of organophosphate poisoning. In this work, we have evaluated reactivation potency of twenty reactivators of different chemical structures in reactivation of VX-inhibited AChE. Rat brain AChE homogenate was used as the appropriate source of the enzyme. According to our results, trimedoxime seems to be the most potent reactivator of VX-inhibited AChE at the concentration 10^-3 M.


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Expression of Peptide Transporters on the Rabbit Retina: A Strategy to Improve Retinal Delivery of Ganciclovir
Soumyajit Majumdar, Sreeraj Macha, Yasser Nashed and Ashim K. Mitra

The objective of this study was to investigate functional expression of peptide transporters on the rabbit retina. In vivo and ex vivo retina/choroidal uptake studies were carried out with New Zealand albino rabbits. [3H]Gly-Sar was used as the model peptide transporter substrate. [3H]Gly-Sar solutions, in the presence and absence of specific inhibitors, were added to the vitreal side of the retina. Results indicate that retinal uptake of [3H]Gly-Sar was significantly inhibited in the presence of other known peptide transporter substrates, such as Gly-Pro and cephalexin. Importantly, valganciclovir, a peptidomimetic prodrug of ganciclovir, also inhibited uptake of [3H]Gly-Sar. These studies therefore, indicate that peptide transporters are functionally expressed on the rabbit retina and retinal concentrations of GCV may be enhanced by targeting these transporters through prodrug derivatization.