Repeatability analysis of the Tetrahymena pyriformis population growth impairment assay

Assessments necessary to ensure the safety of both humans and the environment are challenged by the sheer number of chemicals in use today. Chemical legislation, such as REACH, aims to use alternative methods to reduce the reliance on in vivo animal testing. Consequently, databases such as the TETRATOX database, containing data from the Tetrahymena pyriformis population growth impairment assay, have been used extensively to develop computational models which aid in priority setting and initial hazard assessments. To use any toxicological data, an assessment of quality is required. One important aspect of quality is the repeatability of the assay. This study considered TETRATOX assay data for 85 structurally and mechanistically diverse compounds. The repeatability of replicate determinations was assessed and factors relating to repeatability are discussed. Despite the majority of compounds demonstrating excellent repeatability, it was found that the mechanism of action is likely to be a modulating factor, with compounds acting via electrophilic mechanisms being more likely to exhibit reduced repeatability than those acting via narcotic mechanisms. It is evident from this study that the TETRATOX assay is a robust and highly repeatable assay, suitable for use in toxicological modelling studies and priority setting.     

Combined QSAR/QSPR and molecular docking study on fluoroquinolones to reduce biological enrichment

With the aim of reducing the adverse effects of fluoroquinolones in the environment, a complete design and screening system for the low biological enrichment and high photodegradabilities of 29 fluoroquinolones was established through a three-dimensional quantitative structure–activity relationship (3D-QSAR) model and molecular docking. The interaction mechanisms of the fluoroquinolones with Gram-negative bacteria (DNA gyrase in Escherichia coli) and Gram-positive bacteria (Topoisomerase IV in Staphylococcus aureus) were also evaluated. Consequently, the 3D-QSAR model showed that the 3- and 18-positions of the fluoroquinolones strongly affected their biological enrichment, and that the introduction of electropositive or hydrophobic groups at these positions reduced the logarithm of the octanol-water partition coefficient. Using nadifloxacin as a template, 23 derivatives with lower biological enrichment than nadifloxacin (decreased by 30.12%–94.18%) were designed. Meanwhile, the photodegradabilities of 15 derivatives were increased compared with nadifloxacin. Finally, the further screening by molecular docking of nadifloxacin and the above 15 derivatives with DNA gyrase and Topoisomerase IV showed that 13 of the derivatives had lower biological enrichment (decreased by 0.30%–16.76%) than nadifloxacin in the bacteria.     

Identification of potential inhibitor and enzyme-inhibitor complex on trypanothione reductase to control Chagas disease

Chagas is a parasitic disease with major threat to public health due to its resistance against commonly available drugs. Trypanothione reductase (TryR) is the key enzyme to develop this disease. Though this enzyme is well thought-out as potential drug target, the accurate structure of enzyme-inhibitor complex is required to design a potential inhibitor which is less available for TryR. In this research, we aimed to investigate the advanced drug over the available existing drugs by designing inhibitors as well as to identify a new enzyme-inhibitor complex that may act as a template for drug design. A set of analogues were designed from a known inhibitor Quinacrine Mustard (QUM) to identify the effective inhibitor against this enzyme. Further, the pharmacoinformatics elucidation and structural properties of designed inhibitor proposed effective drug candidates against Chagas disease. Molecular docking study suggests that a designed inhibitor has higher binding affinity in both crystal and modeled TryR and also poses similar interacting residues as of crystal TryR-QUM complex structure. The comparative studies based on in silico prediction proposed an enzyme-inhibitor complex which could be effective to control the disease activity. So our in silico analysis based on TryR built model, Pharmacophore and docking analysis might play an important role for the development of novel therapy for Chagas disease. But both animal model experiments and clinical trials must be done to confirm the efficacy of the therapy.