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A molecular modeling study on 16 1-benzyl tetrahydroisoquinolines (BTHIQs) acting as dopaminergic ligands was carried out. By combining molecular dynamics simulations with ab initio and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of BTHIQs interacting with the human dopamine D2 receptor (D2 DR) is reported here, providing a clear picture of the binding interactions of BTHIQs from both structural and energetic viewpoints. Molecular aspects of the binding interactions between BTHIQs and the D2 DR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental pKi values was obtained, predicting the potential dopaminergic effect of non-synthesized BTHIQs.

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In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB. * PEG400 was used as the vehicle.

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We synthesized and tested 3-chlorotyramine as a ligand of the D2 dopamine receptor. This compound displayed a similar affinity by this receptor to that previously reported for dopamine. In order to understand further the experimental results we performed a molecular modeling study of 3-chlorotyramine and structurally related compounds. By combining molecular dynamics simulations with semiempirical (PM6), ab initio and density functional theory calculations, a simple and generally applicable procedure to evaluate the binding energies of these ligands interacting with the D2 dopamine receptors is reported here. These results provided a clear picture of the binding interactions of these compounds from both structural and energetic view points. A reduced model for the binding pocket was used. This approach allowed us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the Quantum Theory of Atoms in Molecules (QTAIM) technique. Molecular aspects of the binding interactions between ligands and the D2 dopamine receptor are discussed in detail. A good correlation between the relative binding energies obtained from theoretical calculations and experimental IC50 values was obtained. These results allowed us to predict that 3-chlorotyramine possesses a significant affinity by the D2 -DR. Our theoretical predictions were experimentally corroborated when we synthesized and tested 3-chlorotyramine which displayed a similar affinity by the D2 -DR to that reported for DA.

The popular recreational drug MDMA (3,4-methylenedioxy-methamphetamine) has a documented potential as a psychopharmacological clinical and research tool. This is due to its unique ability to promote reprocessing of traumatic memories, empathetic and pro-social states. Although it is established that MDMA exerts its behavioural effects via the serotonin transporter (SERT), the ligand-protein molecular interplay remains elusive. In order to shed light on the binding of MDMA and its primary congeneric entactogens (MDA, MBDB and MDAI), we first combined induced fit with Monte Carlo simulations. The computed interaction energies of the models correlated well with experimental activities ( adj R 2 ¼ 0.78). Then we carried out 'ensemble binding space docking' on trajectories generated by interpolation of experimentally derived structures of the hSERT from the outward-open, and the occluded, to the inward-open states. This approach revealed low-energy alternative binding modes, suggesting high occupancy of the central site, yet considerable MDMA mobility within it, favouring the paroxetine-like orientation. Finally, we designed a pharmacophore that may be used to recognise hSERT-mediated serotonin releasers and uptake inhibitors of diverse chemical structure, identifying their active conformations and interacting residues. We conclude that the conserved amine-Asp98 ionic and edge-to-face π-π interactions are crucial to the mode of action of MDMA on the hSERT, underscoring the contributions of Tyr95 and gating residues Phe341, Tyr176 and Phe335. Amenable to experimental testing, our modelling may aid the rational design of novel entactogenic compounds and contribute to the understanding of an action mechanism, common and typical of psychotropic agents.