Molecular docking of a series of peptidomimetics in the trypanothione binding site of T. cruzi trypanothione reductase.

Chagas' disease (CD) has been responsible for many deaths and disabilities mainly in South America. Currently, 40 million people are at risk of acquiring this disease and, existing therapies are still unsatisfactory, presenting harsh side effects. Therefore, the development of new chemical entities to reverse this state is critical. A series of peptidomimetics, developed by Mc Kie et al. (2001) [11], showed a reversible and competitive inhibition against Trypanosoma cruzi Trypanothione Reductase (TR). These inhibitors may be used as basis of lead compounds in the design of new drug candidates for the treatment of CD. In this work, we have docked this series of peptidomimetics into the TR binding site, using the FlexX algorithm as implemented in the Sybyl program, in order to access the binding mode of this class of compounds in the target enzyme.

3D-QSAR CoMFA of a series of DABO derivatives as HIV-1 reverse transcriptase non-nucleoside inhibitors.

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by comparative molecular field analysis (CoMFA) in order to derive three-dimensional quantitative structure-activity relationship (3D-QSAR) models. The CoMFA study has been performed with a training set of 59 compounds, testing three alignments and four charge schemes (DFT, HF, AM1, and PM3) and using defaults probe atom (Csp (3), +1 charge), cutoffs (30 kcal.mol (-1) for both steric and electrostatic fields), and grid distance (2.0 A). The best model ( N = 59), derived from Alignment 1 and PM3 charges, shows q (2) = 0.691, SE cv = 0.475, optimum number of components = 6, r (2) = 0.930, SEE = 0.226, and F-value = 115.544. The steric and electrostatic contributions for the best model were 43.2% and 56.8%, respectively. The external predictive ability (r (2) pred = 0.918) of the resultant best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, attention should be taken in order to select a substituent for the 4-oxopyrimidine ring, since, as revealed by the best CoMFA model, there are a steric restriction at the C2-position, a electron-rich group restriction at the C6-position ( para-substituent of the 6-benzyl group), and a steric allowed region at the C5-position.

On the structure, interactions, and dynamics of bound VEGF.

The vascular endothelial growth factor (VEGF) is believed to be the most important protein in the regulation of the angiogenic cascade. Thus, exploring the structure and dynamical properties of this growth factor and the influence of receptor and inhibitor binding to these properties may reveal new insights on VEGF's biological process and inhibition opportunities. Here we describe an analysis of molecular dynamics simulations of VEGF bound to the Flt-1 receptor, VEGF bound to the v107 peptide inhibitor, and also VEGF bound to a mutant v107. We analyze the effects of binding to VEGF regarding three aspects: structure, interactions, and dynamics. We found that the structure of VEGF is not significantly perturbed upon binding. We analyze the individual contribution of the VEGF residues to the total interaction energy of binding to Flt-1 and v107. We also compare dynamical variables such as thermal fluctuations and correlations with those of the unbound form. We found that receptor binding is able to promote stronger perturbations on the VEGF dynamical behavior than VEGF inhibitor binding. VEGF motions in the receptor bound complex are shown to be less correlated than motions of unbound VEGF. The work addresses the changes on conformational flexibility of the isolated VEGF upon binding, as well as changes in structure and side-chain rearrangements.