Molecular features for antitrypanosomal activity of thiosemicarbazones revealed by OPS-PLS QSAR studies

A quantitative structure-activity relationship analysis was employed to explore the relationship between the molecular structure of thiosemicarbazone analogues and the inhibition of the cysteine protease cruzain, a validated target for Chagas’ disease treatment. A data set containing 53 thiosemicarbazone derivatives was used to produce a quantitative model for activity prediction of unknown compounds. Several electronic descriptors were obtained through DFT calculations, along with a large amount of Dragon descriptors. The ordered predictor selection (OPS) algorithm was employed to select the most relevant descriptors to perform PLS regressions. With this procedure, significant correlation coefficients ('r POT. 2' = 0.85, 'q POT. 2' = 0.78) were achieved. Furthermore, predicted values for an external test set are in good agreement with the experimental results, indicating the potential of the model for untested compounds. Additional validation tests were carried out, indicating that a robust and reliable model was obtained to be used in the design of new thiosemicarbazones with improved cruzain inhibition potential.FAPESPCAPESCNP

Simulação do espectro de absorção UV do filtro solar p-metoxicinamato de etilexila empregando métodos teóricos (TD-DFT)

FAPESP (11/11499-0)Res. MED06

A mosaic-structured framework applied in the healthy food design: insights from integrated in silico and in vitro approaches

Agrifood system technologies have enabled the development of novel foods with enhanced nutritional composition. Herein, we provide an overview of food model/prototype development by placing natural compounds (NCs) as an inspiration source through the combination of multidisciplinary approaches and food technologies. To design healthy foods, we propose that these interlinked technologies derived from applied fields, such as nutrition, chemical synthesis, pharmacology and food technology should be combined with biological system analyses. Food molecule development is a slow process with mandatory steps based on desired bioactive properties, which is challenged by food matrix diversity and the difficulty of reconstituting its biosynthetic pathways. Overcoming these challenges should be the primary trend in food science, leading to more sustainable processes and health benefits.</p

QSAR studies on the human sirtuin 2 inhibition by non-covalent 7,5,2-anilinobenzamide derivatives

Sirtuin 2 is a key enzyme in gene expression regulation that is often associated with tumor proliferation control and therefore is a relevant anticancer drug target. Anilinobenzamide derivatives have been discussed as selective sirtuin 2 inhibitors and can be developed further. In the present study, hologram and three-dimensional quantitative structure–activity relationship (HQSAR and 3D-QSAR) analyses were employed for determining structural contributions of a compound series containing human sirtuin-2-selective inhibitors that were then correlated with structural data from the literature. The final QSAR models were robust and predictive according to statistical validation (q2 and r2pred values higher than 0.85 and 0.75, respectively) and could be employed further to generate fragment contribution and contour maps. 3D-QSAR models together with information about the chemical properties of sirtuin 2 inhibitors can be useful for designing novel bioactive ligands

Synthetic Curcumin Analogues Present Antiflavivirus Activity In Vitro with Potential Multiflavivirus Activity from a Thiazolylhydrazone Moiety

Arboviral diseases caused by flaviviruses, such as dengue, are a continuing threat and major concern worldwide, with over three billion people estimated to be living with the risk of dengue virus (DENV) infections. There are thus far no antiviral drugs available for treatment, and limited or no vaccines are available. Curcumin and seven synthetic analogues were evaluated for their antiviral activity against dengue virus serotype 2, yellow fever virus and Zika virus, as well as for their cytotoxicity in Vero cells, both by employing MTT assays. Compounds 6 and 7, which present a thiazolylhydrazone moiety, showed moderate activity against all three flaviviruses, with selectivity index (SI) values up to 4.45. In addition, the envelope protein (E) was predicted as the potential target inhibited by both compounds, supported by molecular docking and dynamics simulation analysis. We hope that this data can contribute to the development of new curcumin antiviral analogues in the near future and can help in the search for new promising compounds as potential therapeutic agents to treat flaviviruses infections

Convergent QSAR studies on a series of NK₃ receptor antagonists for schizophrenia treatment

<p>The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK₃) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK₃ antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (<i>q²= </i>0.810 and <i>r²</i>= 0.929) and acceptable HQSAR and CoMSIA models (HQSAR <i>q²= </i>0.644 and <i>r²</i>= 0.910; CoMSIA <i>q²</i>= 0.691, <i>r²</i>= 0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand–receptor interactions. These findings may contribute to develop potential NK₃ receptor antagonists for schizophrenia.</p