N-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)-1H-indazole-3-carboxamide (D2AAK3) as a potential antipsychotic: In vitro, in silico and in vivo evaluation of a multi-target ligand.

Schizophrenia is a mental illness of not adequately understood causes that is not satisfactorily enough treated by current antipsychotics. In search for novel potential antipsychotics we performed structure-based virtual screening aimed to identify new dopamine D2 receptor antagonists. We found compound D2AAK3 with affinity to dopamine D2 receptor of 115 nM. D2AAK3 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A, 5-HT2A and 5-HT7 receptors, which makes it a good hit for further development as a multifunctional ligand. The compound has also some affinity to M1 and H1 receptors. We used homology modeling, molecular docking and molecular dynamics to study interactions of D2AAK3 with its molecular targets at the molecular level. In behavioral studies D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 min after acute treatment, whereas this effect has no longer been observed 60 min after administration of the studied compound in mice.

Mechanisms of Action of Cassiae Semen for Weight Management: A Computational Molecular Docking Study of Serotonin Receptor 5-HT2C.

Overweight and obesity is a growing global health concern. Current management of obesity includes lifestyle intervention, bariatric surgery and medication. The serotonin receptor, 5-HT2C, is known to mediate satiety, appetite and consumption behaviour. Lorcaserin, an appetite control drug, has demonstrated efficacy in appetite control by targeting 5-HT2C but causes undesirable side effects. This study aimed to explore the potential usage of Cassiae semen (CS), a well-known traditional Chinese medicine used to treat obesity. A computational molecular docking study was performed to determine the binding mechanism of CS compounds to the 5-HT2C receptors in both active, agonist-bound and inactive, antagonist-bound conformations. By comparing binding poses and predicted relative binding affinities towards the active or inactive forms of the receptor, we hypothesise that two of the CS compounds studied may be potent agonists which may mimic the appetite suppression effects of lorcaserin: obtusifoliol and cassiaside B2. Furthermore, two ligands, beta-sitosterol and juglanin, were predicted to bind favourably to 5-HT2C outside of the known agonist binding pocket in the active receptor, suggesting that such ligands may serve as positive allosteric modulators of 5-HT2C receptor function. Overall, this study proposed several CS compounds which may be responsible for exerting anti-obesity effects via appetite suppression by 5-HT2C receptor activation.

Design of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists toward schizophrenia: An integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations.

The extrapyramidal side effects of schizophrenia treatment can be significantly reduced by simultaneously targeting dopamine D2 and serotonin 5-HT2A receptors. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of D2 receptor (CoMFA-1, q2 = 0.767, r2 = 0.969; CoMSIA-1, q2 = 0.717, r2 = 0.978) and 5-HT2A receptor antagonists (CoMFA-2, q2 = 0.703, r2 = 0.946; CoMSIA-2, q2 = 0.675, r2 = 0.916) were successfully constructed using 35 tetrahydropyridopyrimidinone derivatives. Topomer CoMFA and HQSAR models were then constructed to further validate and supplement above models. Results showed that all models had good predictive power and stability. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking and molecular dynamic studies also suggested that the hydrogen bonding, electrostatic and hydrophobic interactions played key roles in the formation of stable binding sites. Meanwhile, several key residues like ASP114, TRP100, PHE389 of dopamine D2 receptor and ASP134, PHE328, TRP324 of serotonin 5-HT2A receptor were identified. Based on above findings, seven compounds were obtained through bioisostere replacement and ten compounds were designed by contour map analysis, in which the predicted activity of compounds S6 and DS2 were equivalent to that of the template compound 15. 3D-QSAR and ADMET predictions indicated that all newly designed compounds had great biological activity and physicochemical properties. Moreover, based on the best pharmacophore model, four compounds (Z1, Z2, Z3 and Z4) with new backbones were obtained by virtual screening. Overall, this study could provide theoretical guidance for the structural optimization, design and synthesis of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists. Abbreviations3D-QSARThree-dimensional quantitative structure-activity relationship5-HT2ARSerotonin 5-hydroxytryptamine 5-HT2A receptor5-HT2CRSerotonin 5-hydroxytryptamine 5-HT2C receptor receptorCADDComputer-aided drug designCoMFAComparative molecular field analysisCoMSIAComparative molecular similarity index analysisD2RDopamine D(2) receptorGPCRG-protein coupled receptorPLSPartial least squares regressionHQSARHologram quantitative structure-activity relationship. Communicated by Ramaswamy H. Sarma.

Predictive in silico studies of human 5-hydroxytryptamine receptor subtype 2B (5-HT2B) and valvular heart disease.

Serotonin (5-hydroxytryptamine, 5-HT) receptors are neuromodulator neurotransmitter receptors which when activated trigger a signal transduction cascade within cells resulting in cell-cell communication. 5-hydroxytryptamine receptor 2B (5-HT2B) is a subtype of the seven members of 5-hydroxytrytamine receptors family which is the largest member of the super family of 7-transmembrane G-protein coupled receptors (GPCRs). Not only do 5-HT receptors play physiological roles in the cardiovascular system, gastrointestinal and endocrine function as well as the central nervous system, but they also play a role in behavioral functions. In particular 5-HT2B receptor is widely spread with regards to its distribution throughout bodily tissues and is expressed at high levels in the lungs, peripheral tissues, liver, kidneys and prostate, just to name a few. Hence 5-HT2B participates in multiple biological functions including CNS regulation, regulation of gastrointestinal motality, cardiovascular regulation and 5-HT transport system regulation. While 5-HT2B is a viable drug target and has therapeutic indications for treating obesity, psychosis, Parkinson's disease etc. there is a growing concern regarding adverse drug reactions, specifically valvulopathy associated with 5-HT2B agonists. Due to the sequence homology experienced by 5-HT2 subtypes there is also a concern regarding the off-target effects of 5-HT2A and 5-HT2C agonists. The concepts of sensitivity and subtype selectivity are of paramount importance and now can be tackled with the aid of in silico studies, especially cheminformatics, to develop models to predict valvulopathy associated toxicity of drug candidates prior to clinical trials. This review has highlighted three in silico approaches thus far that have been successful in either predicting 5-HT2B toxicity of molecules or identifying important interactions between 5-HT2B and drug molecules that bring about valvulopathy related toxicities.