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Aim: Through the application of structure- and ligand-based methods, the authors aimed to create an integrative approach to developing a computational protocol for the rational drug design of potent dual 5-HT 2A /D 2 receptor antagonists without off-target activities on H 1 receptors. Materials & methods: Molecular dynamics and virtual docking methods were used to identify key interactions of the structurally diverse antagonists in the binding sites of the studied targets, and to generate their bioactive conformations for further 3D-quantitative structure-activity relationship modeling. Results & conclusion: Toward the goal of finding multi-potent drugs with a more effective and safer profile, the obtained results led to the design of a new set of dual antagonists and opened a new perspective on the therapy for complex brain diseases.

A wide range of neuropsychological disorders is caused by serotonin 5-HT 2A receptor (5-HT 2A R) malfunction. Therefore, this receptor had been frequently used as target in CNS drug research. To design novel potent 5-HT 2A R antagonists, we have combined ligand-based and target-based approaches. This study was performed on wide range of structurally diverse antagonists that were divided into three different clusters: clozapine, ziprasidone, and ChEMBL240876 derivatives. By performing the 50 ns long molecular dynamic simulations with each cluster representative in complex with 5-HT 2A receptor, we have obtained virtually bioactive conformations of the ligands and three different antagonist-bound, inactive, conformations of the 5-HT 2A R. These three 5-HT 2A R conformations were further used for docking studies and generation of the bioactive conformations of the data set ligands in each cluster. Subsequently, selected conformers were used for 3D-Quantitative Structure Activity Relationship (3D-QSAR) modelling and pharmacophore analysis. The reliability and predictive power of the created model was assessed using an external test set compounds and showed reasonable external predictability. Statistically significant variables were used to define the most important structural features required for 5-HT 2A antagonistic activity. Conclusions obtained from performed ligand-based (3D-QSAR) and target-based (molecular docking and molecular dynamics) methods were compiled and used as guidelines for rational drug design of novel 5-HT 2A R antagonists.Communicated by Ramaswamy H. Sarma.

Parkinson's disease (PD) is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum. Current treatments alleviate PD symptoms rather than exerting neuroprotective effect on dopaminergic neurons. New drugs targeting the dopaminergic neurons by specific uptake through the human dopamine transporter (hDAT) could represent a viable strategy for establishing selective neuroprotection. Molecules able to increase the bioactive amount of extracellular dopamine, thereby enhancing and compensating a loss of dopaminergic neurotransmission, and to exert neuroprotective response because of their accumulation in the cytoplasm, are required. By means of homology modeling, molecular docking, and molecular dynamics simulations, we have generated 3D structure models of hDAT in complex with substrate and inhibitors. Our results clearly reveal differences in binding affinity of these compounds to the hDAT in the open and closed conformations, critical for future drug design. The established in silico approach allowed the identification of promising substrate compounds that were subsequently analyzed for their efficiency in inhibiting hDAT-dependent fluorescent substrate uptake, through in vitro live cell imaging experiments. Taken together, our work presents the first implementation of a combined in silico/in vitro approach enabling the selection of promising dopaminergic neuron-specific substrates.