Structural basis for selective inhibition of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase: Molecular docking and 3D QSAR studies

The glycolytic enzyme glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) is as an attractive target for the development of novel antitrypanosomatid agents. In the present work, comparative molecular field analysis and comparative molecular similarity index analysis were conducted on a large series of selective inhibitors of trypanosomatid GAPDH. Four statistically significant models were obtained (r(2) > 0.90 and q(2) > 0.70), indicating their predictive ability for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values were in good agreement with the experimental results. Molecular modeling studies provided further insight into the structural basis for selective inhibition of trypanosomatid GAPDH.

A comparative study on the effects of the benzodiazepine midazolam and the dopamine agents, apomorphine and sulpiride, on rat behavior in the two-way avoidance test

In recent years. studies in behavioral pharmacology have shown the involvement of dopaminergic mechanisms in avoidance behavior as assessed by the two-way active avoidance test (CAR). Changes in dopaminergic transmission also occur in response to particularly threatening challenges. However, studies on the effects of benzodiazepine (BZD) drugs ill this test are still unclear. Given the interplay of dopamine and other neurotransmitters in the neurobiology of anxiety and schizophrenia the aim of this work was to evaluate the effects of systemic administration of midazolam, the dopaminergic agonist apomorphine, and the D(2) receptor antagonist sulpiride using the CAR, a test that shows good sensitivity to typical neuroleptic drugs. Whereas midazolam did not alter the avoidance response. apomorphine increased and sulpiride reduced them in this test. Escape was not affected by any drug treatments. Heightened avoidance was not associated with the increased motor activity caused by apomorphine. In contrast with the benzodiazepine midazolam, activation of post-synaptic D(2) receptors with apomorphine facilitates, whereas the D(2) receptor antagonism with sulpiride inhibited the acquisition of the avoidance behavior. Together, these results bring additional evidence for a role of D(2) mechanisms in the acquisition of the active avoidance. (C) 2009 Elsevier Inc. All rights reserved.

Comparative bioavailability of cefuroxime axetil suspension formulations administered with food in healthy subjects

Objective: To assess the comparative bioavailability of two formulations (250 mg/5 mL suspension) of cefuroxime axetil (CAS 64544-07-6), administered with food, in healthy volunteers of both sexes. Methods: The study was conducted using an open, randomized, two-period crossover design with a 1-week washout interval. Plasma samples were obtained for up to 12 h post dose. Plasma cefuroxime axetil concentrations were analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) with negative ion electrospray ionization using multiple reactions monitoring (MRM). From the cefuroxime axetil plasma concentration vs. time curves, the following pharmacokinetic parameters were obtained: AUC(last) and C(max). Results: The limit of quantification was 0.1 mu g/mL for plasma cefuroxime axetil analysis. The geometric mean and 90% confidence interval CI of test/reference product percent ratios were: 106.1% (100.8%-111.8%) for C(max), 109.4% (104.8%-114.2%) for AUC(last). Conclusion: Since the 90% Cl for AUC(last) and C(max) ratios were within the 80-125 % interval proposed by the US FDA, it was concluded that cefuroxime axetil (test formulation, 250 mg/5 mL suspension) was bioequivalent to a reference formulation under fed conditions, for both the rate and extent of absorption.

Comparative molecular field analysis of a series of inhibitors of HIV-1 protease

Several protease inhibitors have reached the world market in the last fifteen years, dramatically improving the quality of life and life expectancy of millions of HIV-infected patients. In spite of the tremendous research efforts in this area, resistant HIV-1 variants are constantly decreasing the ability of the drugs to efficiently inhibit the enzyme. As a consequence, inhibitors with novel frameworks are necessary to circumvent resistance to chemotherapy. In the present work, we have created 3D QSAR models for a series of 82 HIV-1 protease inhibitors employing the comparative molecular field analysis (CoMFA) method. Significant correlation coefficients were obtained (q(2) = 0.82 and r(2) = 0.97), indicating the internal consistency of the best model, which was then used to evaluate an external test set containing 17 compounds. The predicted values were in good agreement with the experimental results, showing the robustness of the model and its substantial predictive power for untested compounds. The final QSAR model and the information gathered from the CoMFA contour maps should be useful for the design of novel anti-HIV agents with improved potency.