Identification of chiral selectors for improved enantioseparation based on molecular interaction fields

Chiral sulfoxide drugs such as omeprazole, lansoprazole and pantoprazole were chromatographed on three chiral stationary phases (CSP), using amylose tris-(phenylcarbamate) derivatives in the reversed-phase mode. The retention factors (k) and chromatographic partition coefficients (k_w), obtained by extrapolation of the first according to the linear Snyder equation, were analyzed employing molecular interaction fields (MIF) of eluted analytes. Based on the generated MIF, chiral selectors could be identified for improving enantiomeric separation performance of the respective sulfoxides. The method is useful for predicting the complementarities between CSP and analytes, and thus to help the selection of appropriate stationary phases prior to their preparation.     

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 ( r2 > 0.90 and q2 > 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.     

Neuropeptide delivery to the brain: a von Willebrand factor signal peptide to direct neuropeptide secretion

Background  

Multiple neuropeptides, sometimes with opposing functions, can be produced from one precursor gene. To study the roles of the different neuropeptides encoded by one large precursor we developed a method to overexpress minigenes and establish local secretion.     

A partial least squares regression study with antioxidant flavonoid compounds

The quantitative structure-activity relationship of a set of 19 flavonoid compounds presenting antioxidant activity was studied by means of PLS (Partial Least Squares) regression. The optimization of the structures and calculation of electronic properties were done by using the semiempirical method AM1. A reliable model (r ²=0.806 and q ²=0.730) was obtained and from this model it was possible to consider some aspects of the structure of the flavonoid compounds studied that are related with their free radical scavenging ability. The quality of the PLS model obtained in this work indicates that it can be used in order to design new flavonoid compounds that present ability to scavenge free radicals.     

Fragment-based and classical quantitative structure–activity relationships for a series of hydrazides as antituberculosis agents

Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. Multidrug-resistant Mycobacterium tuberculosis is an emerging problem of great importance to public health, and there is an urgent need for new anti-TB drugs. In the present work, classical 2D quantitative structure-activity relationships (QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 91 isoniazid derivatives. Significant statistical models (classical QSAR, q (2) = 0.68 and r (2) = 0.72; HQSAR, q (2) = 0.63 and r (2) = 0.86) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 24 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, [Formula: see text] ; classical QSAR, [Formula: see text]).     

YOYO as a Dye to Track Penetration of LK15 DNA Complexes in Spheroids: Use and Limits

To elucidate the reasons underlying the poor penetration of non-viral vectors in tissues, relating transport properties to physico-chemical parameters of vectors may be crucial. These properties can be influenced by the presence of multiples labels that are used. Therefore utilizing a vector with minimum of labels preferably not more than one is important to studying penetration in tissues. The cell impermeant bisintercalating dye YOYO-1 was found suitable to both monitor the formation of complexes between DNA and an amphipathic peptide LK15 and, to track their penetration in HCT116 spheroids by confocal microscopy. The results revealed a limited decrease of fluorescence ascribed to the high affinity of YOYO-1 to bind DNA. The residual fluorescence of complexes can be exploited to monitor penetration into spheroids, after correction for YOYO-1 attenuation, and to revealing hyaluronidase-induced reduced binding. Hence high affinity dyes such as YOYO-1 with inefficiently quenched fluorescence may be important to establish a relation between novel medicines characteristics and penetration in tissues.     

Structure-based approach for the study of estrogen receptor binding affinity and subtype selectivity

Estrogens exert important physiological effects through the modulation of two human estrogen receptor (hER) subtypes, alpha (hERalpha) and beta (hERbeta). Because the levels and relative proportion of hERalpha and hERbeta differ significantly in different target cells, selective hER ligands could target specific tissues or pathways regulated by one receptor subtype without affecting the other. To understand the structural and chemical basis by which small molecule modulators are able to discriminate between the two subtypes, we have applied three-dimensional target-based approaches employing a series of potent hER-ligands. Comparative molecular field analysis (CoMFA) studies were applied to a data set of 81 hER modulators, for which binding affinity values were collected for both hERalpha and hERbeta. Significant statistical coefficients were obtained (hERalpha, q(2) = 0.76; hERbeta, q(2) = 0.70), indicating the internal consistency of the models. The generated models were validated using external test sets, and the predicted values were in good agreement with the experimental results. Five hER crystal structures were used in GRID/PCA investigations to generate molecular interaction fields (MIF) maps. hERalpha and hERbeta were separated using one factor. The resulting 3D information was integrated with the aim of revealing the most relevant structural features involved in hER subtype selectivity. The final QSAR and GRID/PCA models and the information gathered from 3D contour maps should be useful for the design of novel hER modulators with improved selectivity.     

Vacuum moulding of a superplastic in two dimensions

A mathematical model is proposed for the process of vacuum superplasticforming. The model exploits the fact that in most industrialapplications the sheet aspect ratio (thickness/sheet width)is small. After an initial consideration of some of the moregeneral properties and the literature of superplastic materials,the elastic/plastic deformation of an internally-inflated thin-walledcylinder is examined. Plates of arbitrary geometry are thenconsidered. A quasisteady model in which the sheet moves througha sequence of steady states is developed. Some simplified closed-formsolutions are examined, but for general cases a system of nonlinearpartial differential equations must be solved numerically. Anefficient and accurate semi-explicit numerical scheme is proposedand a simplified stability analysis is presented; the methodis then used to compute properties of superplastic vacuum mouldedsheets in a number of practically motivated cases.