Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies.

HIGHLIGHTS Many CNS targets are being explored for multi-target drug designNew databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compoundsQSAR, virtual screening and docking methods increase the potential of rational drug design The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D1-R/D2-R/5-HT2A -R/H3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs

High fructose led to bipolar-like phenotype in adolescent rats

39 p.-5 fig.-1 tab.BACKGROUND AND PURPOSE: Children and adolescents are the top consumers of high fructose corn syrup (HFCS) sweetened beverages. Even though the cardiometabolic consequences of HFCS consumption in adolescents are well known, the neuropsychiatric consequences have yet to be determined.EXPERIMENTAL APPROACH: Adolescent rats were fed for a month with 11% weight/volume carbohydrate containing HFCS solution, which is similar to the sugar sweetened beverages of human consumption. The metabolic, behavioural and electrophysiologic characteristics of HFCS-fed rats were determined. Furthermore, the effects of TDZD-8, a highly specific GSK-3 inhibitor, on the HFCS-induced alterations were further explored.KEY RESULTS: HFCS-fed adolescent rats displayed bipolar-like behavioural phenotype with hyperexcitability in hippocampal CA3-CA1 synapses. This hyperexcitability was associated with increased presynaptic release probability and increased readily available pool of AMPA receptors to be incorporated into the postsynaptic membrane, due to decreased expression of the neuron-specific alpha3-subunit of Na+ /K+ -ATPase (NKA) and an increased ser845-phosphorylation of GluR1 subunits of AMPA receptors, respectively. TDZD-8 treatment was found to restore behavioural and electrophysiological disturbances associated with HFCS consumption by inhibition of GSK-3, the most probable mechanism of action of lithium for its mood-stabilizing effects.This study shows that HFCS consumption in adolescent rats led to bipolar‐like behavioural phenotype with neuronal hyperexcitability, which is known to be one of the earliest endophenotypic manifestations of bipolar disorder. Inhibition of GSK‐3 with TDZD‐8 attenuated hyperexcitability and restored HFCS‐induced behavioural alterations.Funding from Hacettepe University Scientific Research Project Coordination Unit (Grant no. TSA-2017-15515 to Yildirim Sara) and partial funding from MINECO (Grant no. SAF2012-37979-C03-01 and SAF2016-76693-R to Ana Martinez) are acknowledgedPeer reviewe