Maria Cristina Andreazza Costa

SAR ANALYSIS OF SYNTHETIC NEOLIGNANS AND RELATED COMPOUNDS WHICH ARE ANTI-LEISHMANIASIS ACTIVE COMPOUNDS USING PATTERN RECOGNITION METHODS

Abstract Potentially active new neolignan and analogues against leishmaniasis are proposed. Structure-activity relationship (SAR) techniques were employed. Physicochemical properties such as log P , molecular volume, atomic charge and quantum chemical parameters were calculated for a group of synthetic substances for which the biological activities against leishmaniasis are known. Only about half a dozen out of more than twenty parameters were found to be efficient for the classification of the compounds into active and inactive groups.

A comparative study of principal component and linear multiple regression analysis in SAR and QSAR applied to 1,4-dihydropyridine calcium channel antagonists (nifedipine analogues)

Abstract The method of principal component analysis was shown to be capable of classifying 1,4-dihydropyridine derivatives into high active and low active groups for various different sets of compounds. Mainly quantum chemical parameters were used with this method. The kind of parameters employed by the method were found to be different to those employed by linear multiple regression analysis for identical sets of compounds.

CONFORMATIONAL ANALYSIS OF SYNTHETIC NEOLIGNANS ACTIVE AGAINST LEISHMANIASIS, USING THE MOLECULAR MECHANICS METHOD (MM2)

Conformational analysis of 20 neolignans was performed to determine the most probable conformer that may fit the receptor. The molecular mechanics method (MM2) was employed to construct conformational maps in both a vacuum and a biological environment. Boltzmanns distribution among several local minima was calculated.

Conformation of neolignans that bind to the arginine residue in adenosine-kinase from Leishmania donovani

Most probable conformation of synthetic neolignans that are active against visceral leishmaniasis is proposed. It is based upon an assumption that the receptor of the neolignans is the arginine residue in the adenosine-kinase from Leishmania donovani. A planar form (the two phenyl rings are stretched out) of the neolignans is most likely a preferred receptor site conformation.

Neolignan analogues tested against leishmaniasis. A study of structure–activity relationships and a proposal for the shape of the receptor cavity

An explanation for the activity/inactivity of some neolignans against Leishmania donovani is presented, employing molecular modeling techniques. The electrostatic potential map for all of the active and inactive neolignans was obtained and the shape of the cavity of the active site was estimated. We tried to explain the low activity of a neolignan using the estimated cavity. Pattern recognition methods were applied in order to establish a model that is capable to discriminate the active neolignans to the inactive ones. We found that the activity/inactivity of the compounds are strongly related with the electronic physicochemical descriptors.

Core electron binding energy (CEBE) shifts as descriptors in structure activity relationship (SAR) analysis of neolignans tested against Leishmania donovani

Abstract Core electron binding energy shifts (ΔCEBEs) of carbon atoms calculated with the semi-empirical Hydrogenic Atoms in Molecules, version 3, method were shown to serve as a useful descriptor for structure activity relationship analysis of 12 neolignans studied. Using five selected ΔCEBEs of carbon atoms in the two phenyl rings of the compounds, the compounds were well separated by pattern recognition methods such as principal component analysis and SIMCA.

In vitro cytotoxicity and structure-activity relationship approaches of ent-kaurenoic acid derivatives against human breast carcinoma cell line

In this study, ent-kaurenoic acid derivatives were obtained by microbial transformation methodologies and tested against breast cancer cell lines (MCF-7). A multivariate quantitative-structure activity relationship (QSAR) analysis was performed taking into account both microbial transformation derivatives and other analogues previously reported in literature to give some insight into the main features behind the cytotoxic activity displayed by kaurane-type diterpenes against MCF-7 cells. The partial least square regression (PLS) method was employed in the training set and the best PLS model was built with a factor describing 69.92% of variance and three descriptors (logP, εHOMO and εHOMO-1) selected by the Ordered Predictors Selection (OPS) algorithm. The QSAR model provided reasonable regression (Q2 = 0.64, R2 = 0.72, SEC = 0.29 and SEV = 0.33). The model was validated by leave-N-out cross-validation, y-randomization and external validation (R2pred = 0.89 and SEP = 0.27). The selected descriptors indicated that the activity was mainly related to electronic parameters (HOMO and HOMO-1 molecular orbital energies), as well as to logP. These findings suggest that higher activity values are directly related with both higher logP and frontier orbital energy values. The positive relationship between these orbitals and the activity suggests that the ent-kaurenoic acid analogues interaction with the target involves charge displacement, which is entirely consistent with the literature. Based on these findings, three compounds were proposed and one of them was synthesized and tested. The experimental result confirmed the activity predicted by the model.

Quantification of mineral composition of Brazilian bee pollen by near infrared spectroscopy and PLS regression

Bee pollen consumption has increased in the last years, mainly due to its nutritional value and therapeutic applications. The quantification of mineral constituents is of great importance in order to evaluate both, the toxicity and the beneficial effect of essential elements. The purpose of this work was to quantify the essential elements, Ca, Mg, Zn, P and K, by diffuse reflectance spectra in the near infrared region (NIR) combined with partial least squares regression (PLS), which is a clean and fast method. Reference method used was ICP OES. The determination coefficients for calibration models (R2) were above 0.87 and the mean percent calibration error varied from 5 to 10%. For external validation R2 values were higher than 0.76. The results indicated that NIR spectroscopy can be useful for an approximate quantification of these minerals in bee pollen samples and can be used as a faster alternative to the standard methodologies.

Two-dimensional quantitative structure–activity relationship study of 1,4-naphthoquinone derivatives tested against HL-60 human promyelocytic leukaemia cells

Abstract A series of 50 derivatives of 1,4-naphthoquinone tested against human HL-60 leukaemic cells showed activity at a wide range of concentrations. A multivariate quantitative structure–activity relationship (QSAR) study of 45 compounds was performed through principal component analysis (PCA) and partial least squares (PLS) regression. A good PLS regression model was obtained with two factors describing 60.1% of the total variance, and the selected descriptors were partial atomic charge at carbons 1 and 10 (C1 and C10) and total dipole moment (DIP). The calibration model exhibited the determination coefficient r2 = 0.78 and the standard error of calibration = 0.29. For external validation, r2 and the standard error of prediction were 0.74 and 0.32, respectively. DIP and C1 were the main descriptors for PCA, as well as for PLS, such that the pIC50 value increases when C1 increases and DIP diminishes. The selected descriptors are in accordance with the literature, once C10 and C1 are bound or close to the quinone oxygens involved in the production of radical anions (O2–∙). From the QSAR analysis, the structures of two new naphthoquinones were proposed and their estimated IC50 values were 1.42 and 1.13 μmol L−1.