Studies on the Dual Activity of EGFR and HER-2 Inhibitors Using Structure-Based Drug Design Techniques

HER-2 and EGFR are biological targets related to the development of cancer and the discovery and/or development of a dual inhibitor could be a good strategy to design an effective drug candidate. In this study, analyses of the chemical properties of a group of substances having affinity for both HER-2 and EGFR were carried out with the aim of understanding the main factors involved in the interaction between these inhibitors and the biological targets. Comparative analysis of molecular interaction fields (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were applied on 63 compounds. From CoMFA analyses, we found for both HER-2 (r2 calibration = 0.98 and q2cv = 0.83) and EGFR (r2 calibration = 0.98 and q2cv = 0.73) good predictive models. Good models for CoMSIA technique have also been found for HER-2 (r2 calibration = 0.92 and q2cv = 0.74) and EGFR (r2 calibration = 0.97 and q2cv = 0.72). The constructed models could indicate some important characteristics for the inhibition of the biological targets. New compounds were proposed as candidates to inhibit both proteins. Therefore, this study may guide future projects for the development of new drug candidates for the treatment of breast cancer

A study of neolignan compounds with biological activity against Paracoccidioides brasiliensis by using quantum chemical and chemometric methods

Chemometric (statistical) methods are employed to classify a set of neolignan compounds with activity against Paracoccidioides brasiliensis. The AM1 (Austin Model 1) method was used to calculate a set of molecular descriptors (properties) of the neolignan compounds under study. The descriptors were further analyzed using Principal Components Analysis (PCA), Hierarchical Cluster Analysis (HCA) and K-Nearest Neighbor (KNN) chemometric methods. The PCA and HCA methods were quite efficient to classify the compounds into two groups (active and inactive) and three descriptors were found to be important in the classification: the highest occupied molecular orbital energy (EHOMO), the bond order between C1'-R7 atoms (L14) and the bond order between C5' -R6 atoms (L22). The three variables responsible for the separation between active and inactive compounds are all electronic descriptors, therefore we can conclude that electronic effects should have an important role when one is trying to understand the activity of neolignan compounds against Paracoccidioides brasiliensis.Métodos quimiométricos (estatísticos) são empregados para classificar um conjunto de compostos derivados de neolignanas com atividade biológica contra a Paracoccidioides brasiliensis. O método AM1 (Austin Model 1) foi utilizado para calcular um conjunto de descritores moleculares (propriedades) para os compostos em estudo. A seguir, os descritores foram analisados utilizando os seguintes métodos de reconhecimento de padrões: Análise de Componentes Principais (PCA), Análise Hierárquica de Agrupamentos (HCA) e o método de K-vizinhos mais próximos (KNN). Os métodos PCA e HCA mostraram-se bastante eficientes para classificação dos compostos estudados em dois grupos (ativos e inativos). Três descritores moleculares foram responsáveis pela separação entre os compostos ativos e inativos: energia do orbital molecular mais alto ocupado (EHOMO), ordem de ligação entre os átomos C1'-R7 (L14) e ordem de ligação entre os átomos C5'-R6 (L22). Como as variáveis responsáveis pela separação entre compostos ativos e inativos são descritores eletrônicos, conclui-se que efeitos eletrônicos podem desempenhar um importante papel na interação entre receptor biológico e compostos derivados de neolignanas com atividade contra a Paracoccidioides brasiliensis

Structural Dynamics of DPP-4 and Its Influence on the Projection of Bioactive Ligands

Dipeptidyl peptidase-4 (DPP-4) is a target to treat type II diabetes mellitus. Therefore, it is important to understand the structural aspects of this enzyme and its interaction with drug candidates. This study involved molecular dynamics simulations, normal mode analysis, binding site detection and analysis of molecular interactions to understand the protein dynamics. We identified some DPP-4 functional motions contributing to the exposure of the binding sites and twist movements revealing how the two enzyme chains are interconnected in their bioactive form, which are defined as chains A (residues 40–767) and B (residues 40–767). By understanding the enzyme structure, its motions and the regions of its binding sites, it will be possible to contribute to the design of new DPP-4 inhibitors as drug candidates to treat diabetes

A structure-activity relationship (SAR) study of neolignan compounds with anti-schistosomiasis activity

A set of eighteen neolignan derivative compounds with anti-schistosomiasis activity was studied by using the quantum mechanical semi-empirical method PM3 and other theoretical methods in order to calculate selected molecular properties (variables or descriptors) to be correlated to their biological activities. Exploratory data analysis (principal component analysis, PCA, and hierarchical cluster analysis, HCA), discriminant analysis (DA) and the Kth nearest neighbor (KNN) method were employed for obtaining possible relationships between the calculated descriptors and the biological activities studied and predicting the anti-schistosomiasis activity of new compounds from a test set. The molecular descriptors responsible for the separation between active and inactive compounds were: hydration energy (HE), molecular refractivity (MR) and charge on the C19 carbon atom (Q19). These descriptors give information on the kind of interaction that can occur between the compounds and their respective biological receptor. The prediction study was done with a new set of ten derivative compounds by using the PCA, HCA, DA and KNN methods and only five of them were predicted as active against schistosomiasis.Um conjunto de dezoito compostos de neolignanas com atividade antiesquistossomose foi estudado com o método semi-empírico PM3 e outros métodos teóricos com o intuito de avaliar algumas propriedades (variáveis ou descritores) moleculares selecionadas e correlacioná-las com a atividade biológica. Análise exploratória dos dados (análise de componentes principais, PCA, e análise hierárquica de agrupamentos, HCA), análise discriminante (DA) e o método KNN foram utilizados na obtenção de possíveis correlações entre os descritores calculados e a atividade biológica em questão e na predição da atividade antiesquistossimose de algumas moléculas teste. Os descritores moleculares responsáveis pela separação entre os compostos ativos e inativos foram: energia de hidratação (HE), refratividade molecular (MR) e carga sobre o átomo C19 (Q19). Estes descritores fornecem informações a respeito do tipo de interação que pode ocorrer entre os compostos e seu respectivo receptor biológico. Após a construção do modelo para compostos ativos e inativos, os métodos PCA, HCA, DA e KNN foram empregados em um estudo de predição. Foram estudados 10 novos compostos e somente 5 deles foram classificados como ativos contra esquistossomose

Spectral Region Optimization for Raman-Based Optical Biopsy of Inflammatory Lesions

Objective: The biochemical alterations between inflammatory fibrous hyperplasia (IFH) and normal tissues of buccal mucosa were probed by using the FT-Raman spectroscopy technique. The aim was to find the minimal set of Raman bands that would furnish the best discrimination. Background: Raman-based optical biopsy is a widely recognized potential technique for noninvasive real-time diagnosis. However, few studies had been devoted to the discrimination of very common subtle or early pathologic states as inflammatory processes that are always present on, for example, cancer lesion borders. Methods: Seventy spectra of IFH from 14 patients were compared with 30 spectra of normal tissues from six patients. The statistical analysis was performed with principal components analysis and soft independent modeling class analogy cross-validated, leave-one-out methods. Results: Bands close to 574, 1,100, 1,250 to 1,350, and 1,500 cm(-1) (mainly amino acids and collagen bands) showed the main intragroup variations that are due to the acanthosis process in the IFH epithelium. The 1,200 (C-C aromatic/DNA), 1,350 (CH(2) bending/collagen 1), and 1,730 cm(-1) (collagen III) regions presented the main intergroup variations. This finding was interpreted as originating in an extracellular matrix-degeneration process occurring in the inflammatory tissues. The statistical analysis results indicated that the best discrimination capability (sensitivity of 95% and specificity of 100%) was found by using the 530-580 cm(-1) spectral region. Conclusions: The existence of this narrow spectral window enabling normal and inflammatory diagnosis also had useful implications for an in vivo dispersive Raman setup for clinical applications.FAPESPCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)CNP