Docking and 3D-QSAR modeling of cyclin-dependent kinase 5/p25 inhibitors

Structure-based 3D-QSAR approaches (CoMFA and CoMSIA) were applied to understand the structural requirements of the Cyclin-dependent kinase 5/p25 inhibitors. Cyclin-dependent kinase 5 (CDK5) is believed to play an important role in the development of the central nervous system during the process of mammalian embryogenesis. Genetic algorithm based docking program (GOLD) was successfully utilized to orient the compounds inside the binding pocket of the CDK5/p25 structure. The adapted alignment method with the suitable parameters resulted in a reliable model. Furthermore, the final model was robust enough to forecast the activities of test compounds, satisfactorily. The contour maps were produced around the functional groups to understand the SAR requirements. Moreover, we also investigate the structural attributes of the inhibitors which make them selective toward CDK5/p25 over its close counterpart, i.e., CDK2. The study could be helpful to rationalize the new compounds with better inhibition and selectivity profiles against CDK5/p25.     

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.Subject terms: Neuroscience, Neurological disorders     

Optimizing methyl‐eugenol aromatherapy to maximize posttreatment effects to enhance mating competitiveness of male Bactrocera carambolae (Diptera: Tephritidae)

Methyl‐eugenol (ME) (1,2‐dimethoxy‐4‐(2‐propenyl)benzene), a natural phytochemical, did enhance male Bactrocera carambolae Drew & Hancock (Diptera: Tephritidae) mating competitiveness 3 d after ingestion. Enhanced male mating competitiveness can significantly increase the effectiveness of the sterile insect technique (SIT). ME application to mass reared sterile flies by feeding is infeasible. ME application by aromatherapy however, would be a very practical way of ME application in fly emergence and release facilities. This approach was shown to enhance mating competitiveness of B. carambolae 3 d posttreatment (DPT). Despite this added benefit, every additional day of delaying release will reduce sterile fly quality and will add cost to SIT application. The present study was planned to assess the effects of ME‐aromatherapy on male B. carambolae mating competitiveness 1DPT and 2DPT. ME aromatherapy 1DPT or 2DPT did enhance mating competitiveness of B. carambolae males whereas ME feeding 1DPT and 2DPT did not. Male mating competitiveness was enhanced by the ME aromatherapy irrespective if they received 1DPT, 2DPT or 3DPT. ME aromatherapy, being a viable approach for its application, did enhance mating competitiveness of male B. carambolae 1 d posttreatment as ME feeding did 3 d after ingestion.