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The serotonin type 6 receptor (5-HT 6 R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT 6 R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT 6 R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT 6 R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT 6 R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT 6 R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT 6 R and provide insight into the glioprotective properties of 5-HT 6 R neutral antagonists at Gs signaling., Competing Interests: Declaration of competing interest All authors disclose no financial or personal relationships that may be perceived as influencing their work., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The recently developed and used molecular modeling approach to search for privileged amino acids for halogen bonding (XB hot spots) through XSAR sets has been applied to 5-HT 7 R. Herein, among all identified 5-HT 7 R XB hot spots, the S5x42 was employed in a virtual screening protocol as a constraint. Through a designed virtual screening protocol, 63 XSAR sets (156 compounds) were selected from more than 8 million commercially available compounds and examined using in vitro assay toward 5-HT 7 R. A 68% accuracy was found in predicting halogenated derivatives with higher affinity for 5-HT 7 R than their unsubstituted analogs. Moreover, it was observed that a halogen bond formed between S5x42 and a chlorine atom at the 3-position of the arylpiperazine fragment caused the most remarkable, 35.4-fold increase in binding affinity for 5-HT 7 R when compared to the nonhalogenated analog. Interestingly, molecular dynamics simulations showed the formation of a bifurcated halogen bond with S5x42.

A novel approach to the utilization of nuclear magnetic resonance (NMR) spectroscopy data in the prediction of logD through machine learning algorithms is shown. In the analysis, a data set of 754 chemical compounds, organized into 30 clusters, was evaluated using advanced machine learning models, such as Support Vector Regression (SVR), Gradient Boosting, and AdaBoost, and comprehensive validation and testing methods were employed, including 10-fold cross-validation, bootstrapping, and leave-one-out. The study revealed the superior performance of the Bucket Integration method for dimensionality reduction, consistently yielding the lowest root mean square error (RMSE) across all data sets and normalization schemes. The SVR prediction models demonstrated remarkable computational efficiency and low cost, with the best RMSE value reaching 0.66. Our best model outperformed existing tools like JChem Suite's logD Predictor (0.91) and CplogD (1.27), and a comparison with traditional molecular representations yielded a comparable RMSE (0.50), emphasizing the robustness of our NMR data integration. The widespread availability of NMR data in pharmaceutical and industrial research presents an untapped resource for predictive modeling, highlighting the need for accessible methodologies like ours that complement the analytical toolbox beyond conventional 2D approaches. Our approach, designed to leverage the rich spatial data from NMR spectroscopy, provides additional insights and enriches drug discovery and computational chemistry with a freely accessible tool.

The dopamine D4 receptor (D4R) is a promising therapeutic target in widespread diseases, and the search for novel agonists and antagonists appears to be clinically relevant. The mechanism of binding to the receptor (R) for antagonists and agonists varies. In the present study, we conducted an in-depth computational study, teasing out key similarities and differences in binding modes, complex dynamics, and binding energies for D4R agonists and antagonists. The dynamic network method was applied to investigate the communication paths between the ligand (L) and G-protein binding site (GBS) of human D4R. Finally, the fragment molecular orbitals with pair interaction energy decomposition analysis (FMO/PIEDA) scheme was used to estimate the binding energies of L-R complexes. We found that a strong salt bridge with D3.32 initiates the inhibition of the dopamine D4 receptor. This interaction also occurs in the binding of agonists, but the change in the receptor conformation to the active state starts with interaction with cysteine C3.36. Such a mechanism may arise in the case of agonists unable to form a hydrogen bond with the serine S5.46, considered, so far, to be crucial in the activation of GPCRs. The energy calculations using the FMO/PIEDA method indicate that antagonists show higher residue occupancy of the receptor binding site than agonists, suggesting they could form relatively more stable complexes. Additionally, antagonists were characterized by repulsive interactions with S5.46 distinguishing them from agonists.

Alzheimer's disease (AD), a neurodegenerative disorder with a complex aetiology, is the most common memory dysfunction particularly affecting the elderly. Various protein targets have been classified to be involved in the AD treatment, including 5-HT 6 receptor (5-HT 6 R). So far, the 5-HT 6 R ligands obtained by our research group have become a good basis for hydrophobicity modulation to give a chance for more effective action toward AD by additional influence on target enzymes, e.g. cyclin-dependent kinase 5 (CDK5). In the search for 5-HT 6 R agents with additional inhibitory action on the enzyme, a series of 25 new 1,3,5-triazines (7-31) as modifications of lead, 4-[1-(2,5-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (6), was rationally designed. Molecular modelling, synthesis, crystallographic studies, in vitro biological assays and behavioral studies in vivo were performed. The new triazines showed high affinity (K i  < 100 nM) and selectivity for 5-HT 6 R. The most effective one, 4-[1-(2,5-difluorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (8), exhibited the strong antagonistic action towards 5-HT 6 R (K i  = 5 nM, pK b  = 8.16), had an impact on the memory processes in the Novel Object Recognition test and displayed anxiolytic-like activity in the Elevated Plus Maze test in rats. Moreover, it had the antiplatelet effect as well as very good permeability (PAMPA model), high metabolic stability (RLMs) and satisfactory safety in vitro. Although the CDK5 inhibitory effects in vitro for the tested compounds (8, 10, 14, 18, 26-31) missed the potency expected from in silico simulations, the novel antagonist (8) with a very satisfying pharmacological and ADMET profile can serve as a new lead structure in further searches for innovative therapy against AD with accompanying symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT 6 R antagonism and interaction with 5-HT 3 R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT 6 R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. PZ-1922 , but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HT 6 R/5-HT 3 R/MAO-B in AD.

Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT 6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT 6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (K i  < 200 nM) and selectivity towards 5-HT 6 R, with respect to 5-HT 2A R, 5-HT 7 R, and D 2 R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT 6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT 6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The new dual 5HT 1A /5HT 7 receptor ligands were designed based on the purine-2,6-dione scaffold with the fluorine atom. Twenty-one new derivatives were synthesized, and their structure-activity relationship was summarized. Compound 11 (7-(2-(3-fluorophenyl)-2-oxoethyl)-8-((4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione) showed the highest affinity to 5HT 1A R and 5HT 7 R, and was the most potent antagonist of 5-HT 1A R (K b  = 0.26 ± 0.1 nM) which activity can be to reference compound NAN-190 (K b  = 0.26 ± 0.1 nM). The experimentally established physicochemical parameters of compound 11 showed that compound, as slightly ionized in the blood, could penetrate the blood-brain barrier. A molecular docking study showed that the fluorine substitution introduces additional stabilization effects on binding to 5HT 1A /5HT 7 Rs. In animal assays of depression and anxiety, compound 11 revealed activity in terms of dosage compared to marketed psychotropics such as fluoxetine, citalopram, and sertraline., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3K δ ) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity. In this paper, we compare and evaluate the accuracy of our previously described and validated in silico workflow with that of the standard (rigid) molecular docking approach. The findings demonstrated that a properly fitted catalytic (binding) pocket for our chemical cores at the induced-fit docking (IFD) and molecular dynamics (MD) stages, along with QM-derived atomic charges, can be used for activity prediction to better distinguish between active and inactive molecules. Moreover, the standard approach seems to be insufficient to score the halogenated derivatives due to the fixed atomic charges, which do not consider the response and indictive effects caused by fluorine. The proposed computational workflow provides a computational tool for the rational design of novel halogenated drugs.

Salt bridge (SB, double-charge-assisted hydrogen bonds) formation is one of the strongest molecular non-covalent interactions in biological systems, including ligand-receptor complexes. In the case of G-protein-coupled receptors, such an interaction is formed by the conserved aspartic acid (D3.32) residue and the basic moiety of the aminergic ligand. This study aims to determine the influence of the substitution pattern at the basic nitrogen atom and the geometry of the amine moiety at position 4 of 1 H -pyrrolo[3,2- c ]quinoline on the quality of the salt bridge formed in the 5-HT 6 receptor and D 3 receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1 H -pyrrolo[3,2- c ]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HT 6 R affinity and more potent 5-HT 6 R antagonist properties when compared with the previously identified compound PZ-1643 , a dual-acting 5-HT 6 R/D 3 R antagonist; nevertheless, the proposed modifications did not improve the activity at D 3 R. As demonstrated by the in silico experiments, including molecular dynamics simulations, the applied structural modifications were highly beneficial for the formation and quality of the SB formation at the 5-HT 6 R binding site; however, they are unfavorable for such interactions at D 3 R.

Currently, G protein-coupled receptors (GPCRs) constitute a significant group of membrane-bound receptors representing more than 30% of therapeutic targets. Fluorine is commonly used in designing highly active biological compounds, as evidenced by the steadily increasing number of drugs by the Food and Drug Administration (FDA). Herein, we identified and analyzed 898 target-based F-containing isomeric analog sets for SAR analysis in the ChEMBL database-F i SAR sets active against 33 different aminergic GPCRs comprising a total of 2163 fluorinated (1201 unique) compounds. We found 30 F i SAR sets contain activity cliffs (ACs), defined as pairs of structurally similar compounds showing significant differences in affinity (≥50-fold change), where the change of fluorine position may lead up to a 1300-fold change in potency. The analysis of matched molecular pair (MMP) networks indicated that the fluorination of aromatic rings showed no clear trend toward a positive or negative effect on affinity. Additionally, we propose an in silico workflow (including induced-fit docking, molecular dynamics, quantum polarized ligand docking, and binding free energy calculations based on the Generalized-Born Surface-Area (GBSA) model) to score the fluorine positions in the molecule.

This study aimed to synthesize new thioderivative chalcones and analyze their impact on the NF-κB, STAT3, EGFR and Nrf2 signaling pathways in colorectal cancer cells. Among the studied compounds, derivatives 4 and 5 decreased the activation of NF-κB and the expression of the target gene COX-2. In the case of STAT3, we observed the inhibition of activation of this signaling pathway after influencing derivative 4. Increased activation of the Nrf2 signaling pathway was demonstrated for derivatives 5 and 7 in DLD-1 and HCT116 cells. The results of this study indicated that new chalcone derivatives, especially compounds 4, 5, and-to some degree-7, possess potential applications in the prevention of colorectal cancer., (© 2022. The Author(s).)

The main objective of this study was to develop a test for the fast and noninvasive prediagnosis of mood disorders based on the noninvasive analysis of hair samples. The database included 75 control subjects (who were not diagnosed with depression) and 40 patients diagnosed with mood disorders such as depression or bipolar disorder. Both women and men, aged 18-65 years, participated in the research. After taking the hair samples, they were washed (methanol-water-methanol by shaking in a centrifuge for two min) and air-dried in a fume hood. Each hair collection was analyzed using Fourier transform infrared spectroscopy attenuated total reflection (ATR-FTIR) spectroscopy. Subsequently, the results obtained were analyzed based on chemometric methods: hierarchical cluster analysis (HCA) and principal component analysis (PCA). As a results of the research conducted, potential differences were noticed. There was a visible change in the spectra intensity at around 2800-3100 cm -1 and smaller differences around 1460 cm -1 ; the bands can be assigned to protein vibrations. However, these are preliminary studies that provide a good basis for the development of a test for the initial diagnosis of mood disorders.

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This research allowed us to find the first highly potent 5-HT 6 /5-HT 2A receptor (5-HT 6 /5-HT 2A R) dual antagonists in a group of 1,3,5-triazine compounds as a result of an exit beyond the hydrophobic feature of the pharmacophore model for 5-HT 6 R antagonists. Design and synthesis of the series (2-16) of new O- and S-containing ether derivatives of 1,3,5-triazines with the double-ring aromatic region have been performed. The new compounds were examined within the comprehensive pharmacological screening, including: radioligand binding assays, functional and ADMET studies in vitro as well as behavioral tests in rats. Crystallographic aspects and computer-aided structure-activity relationship were analyzed, as well. The comprehensive approach led to selection of compound 12 (4-(4-methylpiperazin-1-yl)-6-(2-(naphthalen-2-ylthio)propan-2-yl)-1,3,5-triazin-2-amine) with the most significant dual 5-HT 6 /5-HT 2A R antagonistic action (5-HT 6 R K i  = 11 nM, 5-HT 2A R K i  = 39 nM). Moreover, the compound 12 has satisfactory ADMETox properties in vitro, i.e.: the high permeability through biological membranes, high metabolic stability, neither mutagenic nor hepatotoxic effects, and moderate ability to inhibit CYP3A4. Above all, 12 showed ability to reverse the pharmacologically-induced (MK-801) memory impairment at low doses (1-3 mg/kg) in Novel Object Recognition (NOR) test in rats. Our results indicate a promising potency of dual 5-HT 6 /5-HT 2A R antagonism in the search for novel strategy to fight Alzheimer's disease, which remains an unmet clinical need., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mutual positioning and non-covalent interactions in anion-aromatic motifs are crucial for functional performance of biological systems. In this context, regular, comprehensive Protein Data Bank (PDB) screening that involves various scientific points of view and individual critical analysis is of utmost importance. Analysis of anions in spheres with radii of 5 Å around all 5- and 6-membered aromatic rings allowed us to distinguish 555 259 unique anion-aromatic motifs, including 92 660 structures out of the 171 588 structural files in the PDB. The use of a scarcely exploited ( x , h ) coordinate system led to (i) identification of three separate areas of motif accumulation: A - over the ring, B - over the ring-substituent bonds, and C - roughly in the plane of the aromatic ring, and (ii) unprecedented simultaneous comparative description of various anion-aromatic motifs located in these areas. Of the various residues considered, i.e. aminoacids, nucleotides, and ligands, the latter two exhibited a considerable tendency to locate in region A via archetypal anion-π contacts. The applied model not only enabled statistical quantitative analysis of space around the ring, but also enabled discussion of local intermolecular arrangements, as well as detailed sequence and secondary structure analysis, e.g. anion-π interactions in the GNRA tetraloop in RNA and protein helical structures. As a purely practical issue of this work, the new code source for the PDB research was produced, tested and made freely available at https://github.com/chemiczny/PDB&#95;supramolecular&#95;search., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Fluorine is a common substituent in medicinal chemistry and is found in up to 50% of the most profitable drugs. In this study, a statistical analysis of the nature, geometry, and frequency of hydrogen bonds (HBs) formed between the aromatic and aliphatic C-F groups of small molecules and biological targets found in the Protein Data Bank (PDB) repository was presented. Interaction energies were calculated for those complexes using three different approaches. The obtained results indicated that the interaction energy of F-containing HBs is determined by the donor-acceptor distance and not by the angles. Moreover, no significant relationship between the energies of HBs with fluorine and the donor type was found, implying that fluorine is a weak HB acceptor for all types of HB donors. However, the statistical analysis of the PDB repository revealed that the most populated geometric parameters of HBs did not match the calculated energetic optima. In a nutshell, HBs containing fluorine are forced to form due to the stronger ligand-receptor neighboring interactions, which make fluorine the "donor's last resort".

Currently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. Herein, we identified in the ChEMBL database and analysed 1554 target-based FSAR sets (non-fluorinated compounds and their fluorinated analogues) comprising 966 unique non-fluorinated and 2457 unique fluorinated compounds active against 33 different aminergic GPCRs. Although a relatively small number of activity cliffs (defined as a pair of structurally similar compounds showing significant differences of activity -ΔpPot > 1.7) was found in FSAR sets, it is clear that appropriately introduced fluorine can increase ligand potency more than 50-fold. The analysis of matched molecular pairs (MMPs) networks indicated that the fluorination of the aromatic ring showed no clear trend towards a positive or negative effect on affinity; however, a favourable site for a positive potency effect of fluorination was the ortho position. Fluorination of aliphatic fragments more often led to a decrease in biological activity. The results may constitute the rules of thumb for fluorination of aminergic receptor ligands and provide insights into the role of fluorine substitutions in medicinal chemistry.

Structural fingerprints and pharmacophore modeling are methodologies that have been used for at least 2 decades in various fields of cheminformatics, from similarity searching to machine learning (ML). Advances in in silico techniques consequently led to combining both these methodologies into a new approach known as the pharmacophore fingerprint. Herein, we propose a high-resolution, pharmacophore fingerprint called Pharmacoprint that encodes the presence, types, and relationships between pharmacophore features of a molecule. Pharmacoprint was evaluated in classification experiments by using ML algorithms (logistic regression, support vector machines, linear support vector machines, and neural networks) and outperformed other popular molecular fingerprints (i.e., ECFP4, Estate, MACCS, PubChem, Substructure, Klekota-Roth, CDK, Extended, and GraphOnly) and the ChemAxon pharmacophoric features fingerprint. Pharmacoprint consisted of 39 973 bits; several methods were applied for dimensionality reduction, and the best algorithm not only reduced the length of the bit string but also improved the efficiency of the ML tests. Further optimization allowed us to define the best parameter settings for using Pharmacoprint in discrimination tests and for maximizing statistical parameters. Finally, Pharmacoprint generated for three-dimensional (3D) structures with defined hydrogens as input data was applied to neural networks with a supervised autoencoder for selecting the most important bits and allowed us to maximize the Matthews correlation coefficient up to 0.962. The results show the potential of Pharmacoprint as a new, perspective tool for computer-aided drug design.

A series of 4-halogeno aniline derivatives was studied employing combined theoretical and experimental methods (i. e. crystal structure analysis and vibrational spectroscopies). This simplified model system was selected to shed light on the impact of fluorine substitution on the formation of noncovalent interactions such as halogen bonds (XBs) and hydrogen bonds (HBs), which are key interactions in fluorinated/halogenated drug-protein complex formation. Comparative analysis of three previously reported and five newly determined crystal structures indicated that, in most cases, 2-fluoro and 2,6-difluoro substitution of 4-X anilines increases the ability of adjacent amine to form strong N-H⋅⋅⋅N HBs. Additionally, fluorine substituents in the difluorinated derivatives are competitive and attractive HB and XB acceptors and increase the probability of halogen-halogen contacts. A peculiar observation was made for 4-iodoaniline and 2,6-difluoro-4-iodoaniline, which form distinct interaction patterns compared to the corresponding 4-Cl and 4-Br analogs. The observed intramolecular N-H⋅⋅⋅F interactions lead to additional NH bands in the FT-IR spectra., (© 2021 Wiley-VCH GmbH.)

In line with recent clinical trials demonstrating that ondansetron, a 5-HT 3 receptor (5-HT 3 R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT 6 receptor (5-HT 6 R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT 3 /5-HT 6 R antagonists. We identified the first-in-class compound FPPQ , which behaves as a 5-HT 3 R antagonist and a neutral antagonist 5-HT 6 R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ , neither 5-HT 6 R inverse agonist SB399885 nor neutral 5-HT 6 R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT 3 R antagonism and 5-HT 6 R antagonism, exemplified by FPPQ , contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT 3 /5-HT 6 receptors and encourage further studies on dual-acting 5-HT 3 /5-HT 6 R antagonists for the treatment of psychiatric disorders.

Depicting a ligand-receptor complex via Interaction Fingerprints has been shown to be both a viable data visualization and an analysis tool. The spectrum of its applications ranges from simple visualization of the binding site through analysis of molecular dynamics runs, to the evaluation of the homology models and virtual screening. Here we present a novel tool derived from the Structural Interaction Fingerprints providing a detailed and unique insight into the interactions between receptor and specific regions of the ligand (grouped into pharmacophore features) in the form of a matrix, a 2D-SIFt descriptor. The provided implementation is easy to use and extends the python library, allowing the generation of interaction matrices and their manipulation (reading and writing as well as producing the average 2D-SIFt). The library for handling the interaction matrices is available via repository http://bitbucket.org/zchl/sift2d ., (© 2021. The Author(s).)

The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT K i  = 5 nM and 3,4-diCl-fluvoxamine 46, SERT K i  = 9 nM, fluoxetine SERT K i  = 31 nM, fluvoxamine SERT K i  = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. 'XSAR library analysis', a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

A series of N -skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT 1A , 5-HT 2A , 5-HT 6 , and D 2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D 2 receptor antagonists with additional 5-HT 6 R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT 6 R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT 6 R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18 , we tried to sort out the difference between ligands exhibiting the D 2 R antagonist function combined with 5-HT 6 R agonism, and mixed D 2 /5-HT 6 R antagonists in murine models of psychosis.

Hydrogen bonds (HBs) directly engaging fluorine has been extensively studied, but the indirect effect of fluorine on adjacent donors and acceptors is poorly understood and still difficult to predict. The indirect and direct effect of the fluorination of aniline on HB patterns observed in monofluoroanilines was studied via experimental (vibrational spectroscopy and crystal structure analysis) and theoretical (ab initio molecular dynamics and electrostatic surface potential) methods. It was found that a fluorine substituent decreases the strength and frequency of N-H⋯N HBs and, at the same time, increases the acidity of CH protons, enhancing the competitiveness of weaker interactions. Additionally, the position of fluorine in the aromatic ring strongly affects the C-F bond length, and a direct intramolecular N-H⋯F HB causes an increase in the N-H bond stability. We also provide a methodology to identify and separate individual HBs concerning the type of donor or acceptor from the ab initio molecular dynamics trajectories., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Serotonin type 6 receptor (5-HT 6 R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1 H -pyrrolo[3,2- c ]quinoline scaffold to provide the 2-phenyl-1 H -pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT 6 R. This modification has changed the compound's activity at 5-HT 6 R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT 6 R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1 H -pyrrole-3-carboxamide might be used as a template for designing 5-HT 6 R inverse agonists.

The process of modern drug design would not exist in the current form without computational methods. They are part of every stage of the drug design pipeline, supporting the search and optimization of new bioactive substances. Nevertheless, despite the great help that is offered by in silico strategies, the power of computational methods strongly depends on the input data supplied at the stage of the predictive model construction. The studies on the efficiency of the computational protocols most often focus on global efficiency. They use general parameters that refer to the whole dataset, such as accuracy, precision, mean squared error, etc. In the study, we examined machine learning predictions obtained for opioid receptors (mu, kappa, delta) and focused on cases for which the predictions were the most accurate and the least accurate. Moreover, by using docking, we tried to explain prediction errors. We attempted to develop a rule of thumb, which can help in the prediction of compound activity towards opioid receptors via docking, especially those that have been incorrectly predicted by machine learning. We found out that although the combination of ligand- and structure-based path can be beneficial for the prediction accuracy, there still remain cases that cannot be reliably predicted by any available modeling method. In addition to challenging ligand- and structure-based predictions, we also examined the role of the application of machine-learning methods in comparison to simple statistical methods for both standard ligand-based representations (molecular fingerprints) and interaction fingerprints. All approaches were confronted in both classification (where compounds were assigned to the group of active and inactive group constructed on the basis of K i values) and regression (where exact K i value was predicted) experiments.

G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e , which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT 6 R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT 6 R ( 7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT 6 R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT 6 R.

The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT 6 receptor (5-HT 6 R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT 6 R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT 6 R at G s signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT 6 R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

In the light of recent lines of evidence, 5-HT 6 R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT 6 R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT 6 R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K i  < 100 nM) and selectivity towards 5-HT 6 R, with respect to 5-HT 2A R, 5-HT 7 R and D 2 R. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HT 6 R affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K i  = 6 nM), very strong 5-HT 6 R antagonistic action (K B  = 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro, was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Vascular endothelial growth factor receptor 2 (VEGFR2) is a key receptor in the angiogenesis process. The VEGFR2 expression is upregulated in many cancers so this receptor is an important target for anticancer agents. In the present paper, we analyse interactions of several dimeric indazoles, previously investigated for anticancer activity, with the amino acids present in the VEGFR2 binding pocket. Using the docking method and MD simulations as well as theoretical computations (SAPT0, PIEDA, semi-empirical PM7), we confirmed that these azoles can efficiently bind into the kinase pocket and their poses can be stabilised by the formation of hydrogen bonds, π-π stacking, π-cation, and hybrid interactions with some amino acids of the kinase cavity like Ala866, Lys868, Glu885, Thr916, Glu917, and Phe918.

A virtual screening campaign aimed at finding structurally new compounds active at 5-HT 6 R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT 6 R K i  = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT 6 R K i  = 25, 5-HT 2A R K i  = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Recently, a computational approach combining a structure-activity relationship library containing pairs of halogenated ligands and their corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was developed and used to search for amino acids frequently targeted by halogen bonding, also known as XB hot spots. However, the analysis of ligand-receptor complexes with halogen bonds obtained by molecular docking provides a limited ability to study the role and significance of halogen bonding in biological systems. Thus, a set of molecular dynamics simulations for the dopamine D 4 receptor, recently crystallized with the antipsychotic drug nemonapride (5WIU), and the five XSAR sets were performed to verify the identified hot spots for halogen bonding, in other words, primary (V5x40), and secondary (S5x43, S5x461 and H6x55). The simulations confirmed the key role of halogen bonding with V5x40 and H6x55 and supported S5x43 and S5x461. The results showed that steric restrictions and the topology of the molecular core have a crucial impact on the stabilization of the ligand-receptor complex by halogen bonding., Competing Interests: The authors declare no conflict of interest.

Though the 5-HT 6 serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HT 6 R ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HT 6 R agents and insufficient "drugability." Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HT 6 R ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and "druglikeness" characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HT 6 R has been performed. "Druglikeness" was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug-drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats' metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the "druglikeness" profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HT 6 R.

A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT 6 R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT 6 R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT 6 R and very high selectivity over 5-HT 1A , 5-HT 2A , 5-HT 7 and D 2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential., (Copyright © 2019. Published by Elsevier Masson SAS.)

This research has provided the most active 5-HT 6 R agents among 1,3,5-triazine derivatives investigated to date and has also identified the world's first selenium-containing 5-HT 6 R ligands. The studies are focused on design, synthesis, biological evaluation and docking-supported SAR analysis for novel 5-HT 6 R agents as derivatives of lead structure 4-(4-methylpiperazin-1-yl)-6-(phenoxymethyl)-1,3,5-triazin-2-amine (7). The lead modifications included an introduction of: (i) various small substituents at benzene ring, (ii) a branched ether linker or (iii) the ether oxygen replacement with other chalcogen (S, Se) or sulfonyl moiety. Hence, a series of new compounds (7-24) was synthesized and examined on their affinities for 5-HT 6 R and selectivity, in respect to the 5-HT 1A R, 5-HT 2A R, 5-HT 7 R and dopamine D 2 receptor, in the radioligand binding assays. For representative most active compounds functional bioassays and toxicity profile in vitro and antidepressant-like activity in vivo were examined. The 2-isopropyl-5-methylphenyl derivative (10) was found as the most active triazine 5-HT 6 R antagonist (K i  = 11 nM). SAR analysis indicated, that an exchange of oxygen to selenium (7 vs. 22), and especially, to sulfur (7 vs. 19) was beneficial to increase both affinity and antagonistic action for 5-HT 6 R. Surprisingly, an introduction of SO 2 caused a drastic decrease of the 5-HT 6 R affinity, which was explained at a molecular level based on docking studies. All in vivo tested compounds (10, 18 and 21) did not show any risk of toxicity in the safety studies in vitro., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Complexes of colchiceine with monovalent cation perchlorates and iodides have been obtained and characterized by spectroscopic methods. DFT and spectroscopic studies reveal that the dihedral angle ω 1-1a-12-12a , crucial for colchicine biological mechanism of action, that is, binding to tubulins depends on the diameter of the complexed metal cation. Biological tests indicated no antifungal properties of colchicine (it was active only toward A.pullulans), in contrast to its derivative-(colchiceine). Complexation of colchiceine with metal cations improved significantly the antifungal potency, even below MIC <1 μg/ml. The colchiceine complexes were more potent than colchiceine, and some of them were even more potent than the fungicidal standard IPBC. The highest potency of colchiceine complexes was noted against A. pullulans (MIC = 0.5 μg/ml). In contrast to the findings concerning antifungal potency, the anticancer studies showed complexes of colchicine more active (~IC 50  = 2 nM) than those of colchiceine (~IC 50  = 6 μM). MDA-MB-231 breast cancer cell lines and human lung fibroblasts CCD39Lu were also tested., (© 2019 John Wiley & Sons A/S.)

In light of the multifactorial origin of neurodegenerative disorders and some body of evidence indicating that pharmacological blockade of serotonin 5-HT 6 and dopamine D 3 receptors might be beneficial for cognitive decline, we envisioned ( S )-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1 H -pyrrolo[3,2- c ]quinoline (CPPQ), a neutral antagonist of 5-HT 6 R, as a chemical template for designing dual antagonists of 5-HT 6 /D 3 receptors. As shown by in vitro experiments, supported by quantum chemical calculations and molecular dynamic simulations, introducing alkyl substituents at the pyrrolidine nitrogen of CPPQ, fulfilled structural requirements for simultaneous modulation of 5-HT 6 and D 3 receptors. The study identified compound 19 (( S )-1-((3-chlorophenyl)sulfonyl)- N -(1-isobutylpyrrolidin-3-yl)-1 H -pyrrolo[3,2- c ]quinolin-4-amine), which was classified as a dual 5-HT 6 /D 3 R antagonist ( K i(5-HT6) = 27 nM, K i(D3) = 7 nM). Compound 19 behaved as a neutral antagonist at G s signaling and had no influence on receptor-operated, cyclin-dependent kinase 5 (Cdk5)-dependent neurite growth. In contrast to the well characterized 5-HT 6 R antagonist intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage induced by doxorubicin, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an index of cell membrane disruption. This feature is of particular importance considering the involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. Biological results obtained for 19 in in vitro tests, translated into procognitive properties in phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in rats.

The 5-HT 7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT 7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, K i 5-HT7 R  = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain C max  = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT 7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The complexes of selected long-chain arylpiperazines with homology models of 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors were investigated using quantum mechanical methods. The molecular geometries of the ligand-receptor complexes were firstly optimized with the Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) method. Next, the fragment molecular orbitals method with an energy decomposition analysis scheme (FMO-EDA) was employed to estimate the interaction energies in binding sites. The results clearly showed that orthosteric binding sites of studied serotonin receptors have both attractive and repulsive regions. In the case of 5-HT 1A and 5-HT 2A two repulsive areas, located in the lower part of the binding pocket, and one large area of attraction engaging many residues at the top of all helices were identified. Additionally, for the 5-HT 7 receptor, the third area of destabilization located at the extracellular end of the helix 6 was found.

A series of 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazines was designed based on previously published 2-amino-4-benzyl-(4-methylpiperazin-1-yl)-1,3,5-triazines in order to evaluate the role of a linker between the triazine moiety and an aromatic substituent for the human serotonin 5-HT 6 receptor affinity. As new linkers two carbon atoms (ethyl or ethenyl) or an oxyalkyl chain (methoxy, 2-ethoxy, 2-propoxy) were introduced. Affinities of the compounds for the 5-HT 6 R as the main target, and for the 5-HT 1A R, 5-HT 7 R and D 2 R as competitive ones, were determined in the radioligand binding assays. Docking to the 5-HT 6 R homology model was performed to support SAR analysis. Results showed that the branching of the methoxyl linker increased affinity for the human 5-HT 6 R whereas an unsaturated bond within the linker dramatically reduced desirable activity. Both experimental and theoretical studies confirmed the previously postulated beneficial role of the aromatic size for interaction with the 5-HT 6 R. Thus, the largest naphthyl moiety yielded the highest activity. In particular, 4-(4-methylpiperazin-1-yl)-6-(1-(naphthalen-1-yloxy)ethyl)-1,3,5-triazin-2-amine (24), the most potent 5-HT 6 R agent found (K i  = 23 nM), can be a new lead structure for further search and development., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although the salt bridge is the strongest among all known noncovalent molecular interactions, no comprehensive studies have been conducted to date to examine its role and significance in drug design. Thus, a systematic study of the salt bridge in biological systems is reported herein, with a broad analysis of publicly available data from Protein Data Bank, DrugBank, ChEMBL, and GPCRdb. The results revealed the distance and angular preferences as well as privileged molecular motifs of salt bridges in ligand-receptor complexes, which could be used to design the strongest interactions. Moreover, using quantum chemical calculations at the MP2 level, the energetic, directionality, and spatial variabilities of salt bridges were investigated using simple model systems mimicking salt bridges in a biological environment. Additionally, natural orbitals for chemical valence (NOCV) combined with the extended-transition-state (ETS) bond-energy decomposition method (ETS-NOCV) were analyzed and indicated a strong covalent contribution to the salt bridge interaction. The present results could be useful for implementation in rational drug design protocols.

A computational approach combining a structure-activity relationship library of halogenated and the corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was used to search for amino acids frequently targeted by halogen bonding (hot spots) in a 5-HT 7 R as a case study. The procedure identified two sets of hot spots, extracellular (D2.65, T2.64, and E7.35) and transmembrane (C3.36, T5.39, and S5.42), which were further verified by a synthesized library of halogenated arylsulfonamide derivatives of (aryloxy)ethylpiperidines. It was found that a halogen bond formed between T5.39 and a bromine atom at 3-position of the aryloxy fragment caused the most remarkable, 35-fold increase in binding affinity for 5-HT 7 R when compared to the nonhalogenated analog. The proposed paradigm of halogen bonding hot spots was additionally verified on D 4 dopamine receptor showing that it can be used in rational drug design/optimization for any protein target.

This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines, with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT₆, 5-HT 1A , 5-HT 2A , 5-HT₇, and dopamine D₂ receptors were evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT₆ receptor conformation space employing two lead structures. It resulted in a consistent binding mode with the activity data. For the most active compounds found in each modification line, anti-obesity and anti-depressive-like activity in vivo, as well as "druglikeness" in vitro, were examined. Two 2-naphthyl compounds ( 18 and 26 ) were identified as the most active 5-HT₆R agents within each lead modification line, respectively. The 5-(2-naphthyl)hydantoin derivative 26 , the most active one in the series (5-HT₆R: K i = 87 nM), displayed also significant selectivity towards competitive G-protein coupled receptors (6⁻197-fold). Docking studies indicated that the hydantoin ring is stabilized by hydrogen bonding, but due to its different orientation, the hydrogen bonds form with S5.44 and N6.55 or Q6.58 for 18 and 26 , respectively. Compound 26 exerted anxiolytic-like and antidepressant-like activities. Importantly, it demonstrated anti-obesity properties in animals fed palatable feed, and did not show toxic effects in vitro.

A series of new semi-synthetic 7-deacetyl-10-alkylthiocolchicne derivatives with ethyl, n -propyl, i-propyl and n -butyl substituents were synthesised and characterised by spectroscopic methods, elemental analysis, DFT calculations and molecular docking simulations. All the synthesized compounds have been tested for fungicidal and anticancer activities against SKOV-3, LoVo, MCF-7, MDA-MB-231 and the lung-derived fibroblast CCD39Lu. All the new colchicine derivatives exhibit significantly higher cytotoxicity towards the SKOV-3 tumour cell line than the natural product - colchicine. The most effective cytotoxic agents were 7-deacetyl-10- n -buthylthiocolchicine and 7-deacetyl-10-i-propylthiocolchicine. Among all the compounds tested, 7-deacetyl-10- n -buthylthiocolchicine exhibited the highest fungicidal activity. Molecular modeling indicated that several mutations found in the β-tubulin unit of the tested fungal strains are crucial for antifungal activity and selectivity of 7-deacetyl-10- n -buthylthiocolchicine. The obtained results may be useful for the development of selective colchicine derivatives as effective fungicidal and/or anticancer drugs.

Based on pyrroloquinoline scaffold bearing 5-HT 2C agonists, a series of arylsulfonamide derivatives of 1H-pyrrolo[2,3-f]quinoline and 1H-pyrrolo[3,2-h]quinoline, substituted at position 3 with tetrahydropyridine, were synthesized and evaluated in vitro for their affinity for 5-HT 6 receptors. A structure-activity relationship study showed that the 1H-pyrrolo[3,2-h]quinoline scaffold was more favorable for 5-HT 6 R binding than the 1H-pyrrolo[2,3-f]quinoline one, suggesting dependence upon the type of condensation of the pyrrole and quinoline rings. As revealed by quantum-chemical calculations and molecular dynamic studies, position of the quinoline nitrogen atom in the planar pyrroloquinoline skeleton might affect the spatial orientation of the arylsulfonyl fragment, as a result of structure stabilization by internal hydrogen bonds., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A series of azinesulfonamide derivatives of long-chain arylpiperazines with variable-length alkylene spacers between sulfonamide and 4-arylpiperazine moiety is designed, synthesized, and biologically evaluated. In vitro methods are used to determine their affinity for serotonin 5-HT 1A , 5-HT 6 , 5-HT 7 , and dopamine D 2 receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT 1A and 5-HT 7 receptor models are then conducted to investigate the conformational preferences of selected serotonin receptor ligands in different environments. The bent conformation of tetramethylene derivatives is found in a solid state, in dimethyl sulfoxide, and as a global energy minimum during conformational analysis in a simulated water environment. Furthermore, ligand geometry in top-scored complexes is also bent, with one torsion angle in the spacer (τ 2 ) in synclinal conformation. Molecular docking studies indicate the role of halogen bonding in complexes of the most potent ligands and target receptors.

In order to search for active and selective serotonin 5-HT 7 R antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of the introduction/deletion and the mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure of 3-(3-(4-(diphenylmethyl)piperazin-1-yl)-2-hydroxypropyl)-5-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione ( 2 , KKB16) were performed. New derivatives ( 4-18 ) were designed and synthesized. X-ray crystallographic analysis of the representative compound 5-(4-fluorophenyl)-3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl]-5-methylimidazolidine-2,4-dione ( 3 ) was performed to support molecular modeling and SAR studies. The affinity for 5-HT 7 R, D 2 R and 5-HT 1A R in radioligand binding assays for the entire series and ADME-Tox parameters in vitro for selected compounds ( 7 , 10 , and 13 ) were evaluated. Molecular docking and pharmacophore model assessment were performed. According to the obtained results, 5-methyl-5-naphthylhydantoin derivatives were found to be the new highly active 5-HT 7 R agents ( K i ≤ 5 nM) with significant selectivity over 5-HT 1A R and D 2 R. On the contrary, the (1-naphthyl)piperazine moiety was gained with the potent dual 5-HT 7 R/5-HT 1A R action ( K i : 11 nM/19 nM).

This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (1, MF-8), as part of the search for potent and selective serotonin 5-HT 7 receptor (5-HT 7 R) agents. New hydantoin derivatives (4-19) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (4), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT 7 R and selectivity over 5-HT 1A R, dopamine D 2 R and α 1 -, α 2 -and β-adrenoceptors. Selected compounds (5-8) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT 7 R in RBA, in particular seven compounds (4, 5, 7, 8 and 10-12,K i  ≤ 10 nM). Antidepressant-like activity in vivo for all tested compounds (5-8) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono-phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT 7 R affinity than the di-phenyl ones., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC 50 values of 0.86, 1.05, and 0.85 μM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i, a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)