Analysis of structure-Caco-2 permeability relationships using a property landscape approach

Understanding the relationship between the chemical structure of bioactive compounds and Caco-2 permeability is of major importance in modern drug discovery. The purpose of this work was to characterize systematically the Caco-2 permeability landscape of a benchmark dataset of 100 molecules using a novel approach based on the emerging concept of property landscape modeling. Pairwise comparisons of the Caco-2 permeability and chemical structures were calculated for all possible combinations in the dataset. To compare the chemical structures, two distinct manners to represent the molecules were employed, namely, continuous properties previously used to derive QSPR models and molecular fingerprints with different designs. We introduce the concept of “permeability cliffs” discussing cases of compounds with high molecular similarity but large permeability difference. All permeability cliffs were regarded as shallow cliffs, since no extreme difference in Caco-2 permeability (less than two log units) was identified in the dataset. A clear dependence of Caco-2 permeability landscape with molecular representation was observed. The current approach can be further extended to model other ADME relevant landscapes.     

Systematic search for benzimidazole compounds and derivatives with antileishmanial effects

Leishmaniasis is a neglected tropical disease that currently affects 12 million people, and over 1 billion people are at risk of infection. Current chemotherapeutic approaches used to treat this disease are unsatisfactory, and the limitations of these drugs highlight the necessity to develop treatments with improved efficacy and safety. To inform the rational design and development of more efficient therapies, the present study reports a chemoinformatic approach using the ChEMBL database to retrieve benzimidazole as a target scaffold. Our analysis revealed that a limited number of studies had investigated the antileishmanial effects of benzimidazoles. Among this limited number, L. major was the species most commonly used to evaluate the antileishmanial effects of these compounds, whereas L. amazonensis and L. braziliensis were used least often in the reported studies. The antileishmanial activities of benzimidazole derivatives were notably variable, a fact that may depend on the substitution pattern of the scaffold. In addition, we investigated the effects of a benzimidazole derivative on promastigotes and amastigotes of L. infantum and L. amazonensis using a novel fluorometric method. Significant antileishmanial effects were observed on both species, with L. amazonensis being the most sensitive. To the best of our knowledge, this chemoinformatic analysis represents the first attempt to determine the relevance of benzimidazole scaffolds for antileishmanial drug discovery using the ChEMBL database. The present findings will provide relevant information for future structure–activity relationship studies and for the investigation of benzimidazole-derived drugs as potential treatments for leishmaniasis.     

Exploring In Vitro Biological Cellular Responses of Pegylated β-Cyclodextrins

βCDPEG5 and βCDPEG2 are two derivatives comprising seven PEG linear chains of 5 and 2 kDa, respectively, conjugated to βCD. As βCDPEGs display different physicochemical properties than their precursors, they could also trigger distinct cellular responses. To investigate the biological behavior of βCDPEGs in comparison to their parent compounds, we performed broad toxicological assays on RAW 264.7 macrophages, MC3T3-E1 osteoblasts, and MDCK cells. By analyzing ROS and NO₂⁻ overproduction in macrophages, we found that βCDPEGs induced a moderate stress response without affecting cell viability. Although MC3T3-E1 osteoblasts were more sensitive than MDCK cells to βCDPEGs and the parent compounds, a similar pattern was observed: the effect of βCDPEG5 on cell viability and cell cycle progression was larger than that of βCDPEG2; PEG2 affected cell viability and cell cycle more than βCDPEG2; cell post-treatment recovery was favorable in all cases, and the compounds had similar behaviors regarding ROS generation. The effect on MDCK cell migration followed a similar pattern. In contrast, for osteoblasts, the interference of βCDPEG5 with cell migration was smaller than that of βCDPEG2; likewise, the effect of PEG2 was shorter than its conjugate. Overall, the covalent conjugation of βCD and PEGs, particularly to yield βCDPEG2, improved the biocompatibility profile, evidencing that a favorable biological response can be tuned through a thoughtful combination of materials. Moreover, this is the first time that an in vitro evaluation of βCD and PEG has been presented for MC3T3-E1 and MDCK cells, thus providing valuable knowledge for designing biocompatible nanomaterials constructed from βCD and PEGs.