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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—FiSAR sets active against 33 different aminergic GPCRs comprising a total of 2163 fluorinated (1201 unique) compounds. We found 30 FiSAR 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. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of a new series of 1,3,5-triazinylpiperazines. • Affinities for receptors: 5-HT 6 , 5-HT 1A and D 2 in radioligand binding assays. • Molecular modeling docking studies to 5-HT 6 receptor homology model. • SAR studies on the role of linkers for the 5-HT 6 receptor affinity. • New lead structure in search for potent 5-HT 6 receptor ligands was found. Abstract 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. [ABSTRACT FROM AUTHOR]

Abstract: The crystal structure of metabotropic glutamate receptor 1 (mGluR1) complexed with 4‐fluoro‐N‐(4‐(6‐(isopropylamino)pyrimidin‐4‐yl)thiazol‐2‐yl)‐N‐methylbenzamide (FITM, a negative allosteric modulator) and its twelve close structural analogs with a broad spectrum of affinities (2.4 nM < IC50 > 10 000 nM) were investigated using quantum mechanical methods. The our own N‐layered integrated molecular orbital and molecular mechanics (ONIOM) was used to optimize the molecular geometries of the receptor with complexed ligands, which were then used to perform the ab initio calculations using the fragment molecular orbitals method with energy decomposition analysis (FMO‐EDA). The results clearly showed that residues Q6603.28 and/or Y8056.55 were the anchoring points for all the studied analogs of FITM, while the H‐bond with T8157.38 determined only the orientation of very active molecules containing an amino substituent in the pyrimidine moiety (e.g., FITM). The orientation of the other parts of ligands resulted from hydrophobic interactions mainly with L7575.44, F8016.51, or W7986.48. The applied ONIOM/FMO–EDA approach facilitated the study of effects related to very small changes in the ligand structure and led to conclusions regarding the significance of individual interactions in the allosteric binding pocket of mGluR1. [ABSTRACT FROM AUTHOR]

Based on pyrroloquinoline scaffold bearing 5-HT 2C agonists, a series of arylsulfonamide derivatives of 1 H -pyrrolo[2,3- f ]quinoline and 1 H- 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 1 H- pyrrolo[3,2- h ]quinoline scaffold was more favorable for 5-HT 6 R binding than the 1 H -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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The work describes a discovery of new chemical family of potent ligands for the 5-HT 6 serotonin receptors. During the search for new histamine H 4 receptor antagonists among 1,3,5-triazine derivatives, compound 2 (4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) was found. Compound 2 , weakly active for the H 4 receptor but fitted in 3/4 of pharmacophore features of the 5-HT 6 R ligand, occurred to be a moderate 5-HT 6 R agent, useful as a lead structure for further modifications. A series of new derivatives ( 3 – 19 ) of the lead 2 was synthesized, evaluated in the radioligand binding assay (RBA) and explored in comprehensive molecular modelling, including both pharmacophore- and structure-based approaches with docking to the homology model of 5-HT 6 R. The most active compounds displayed a potent affinity for the 5-HT 6 R in the nanomolar range (K i = 20–30 nM), some of them ( 4 , 11 and 19 ) were tested in the rat forced swim test that revealed their antidepressant-like effect. SAR-analysis on the basis of both, RBA and docking results, indicated that action on the receptor is related to the hydrophobicity and the size of aromatic moiety substituted by a methylene linker at the position 4 of 1,3,5-triazine. [ABSTRACT FROM AUTHOR]

A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D 2 and serotoninergic 5-HT 1A , 5-HT 2A , 5-HT 6 and 5-HT 7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline ( 21 ), which behaved as D 2 , 5-HT 1A and 5-HT 7 receptor antagonist. In preliminary in vivo studies, compound 21 displayed distinct antipsychotic properties in the MK-801-evoked hyperactivity test in mice at a dose of 10 mg/kg, and exerted antidepressant-like effect in a forced swim test in mice (MED = 0.625 mg/kg, i.p .). [ABSTRACT FROM AUTHOR]

The machine learning-based virtual screening of molecular databases is a commonly used approach to identify hits. However, many aspects associated with training predictive models can influence the final performance and, consequently, the number of hits found. Thus, we performed a systematic study of the simultaneous influence of the proportion of negatives to positives in the testing set, the size of screening databases and the type of molecular representations on the effectiveness of classification. The results obtained for eight protein targets, five machine learning algorithms (SMO, Naïve Bayes, Ibk, J48 and Random Forest), two types of molecular fingerprints (MACCS and CDK FP) and eight screening databases with different numbers of molecules confirmed our previous findings that increases in the ratio of negative to positive training instances greatly influenced most of the investigated parameters of the ML methods in simulated virtual screening experiments. However, the performance of screening was shown to also be highly dependent on the molecular library dimension. Generally, with the increasing size of the screened database, the optimal training ratio also increased, and this ratio can be rationalized using the proposed cost-effectiveness threshold approach. To increase the performance of machine learning-based virtual screening, the training set should be constructed in a way that considers the size of the screening database. [ABSTRACT FROM AUTHOR]

The combination of quantum mechanics/molecular mechanics-driven (QM/MM) molecular docking with binding free-energy calculations was successfully used to reproduce the X-ray geometries of protein-ligand complexes with halogen bonding. The procedure involves quantum-polarized ligand docking (QPLD) to obtain the QM-derived ligand atomic charges in the protein environment at the B3PW91/cc-pVTZ level and the MM/GBSA (generalized-Born/surface area) algorithm to calculate the binding free energies of resultant complexes. The performance was validated using a set of 106 X-ray complexes and compared with the Glide and AutoDock VinaXB scoring functions in terms of RMSD and the reconstruction of halogen-bond geometry (distance and σ-hole angle). The results revealed that docking and scoring using the QPLD-GBSA procedure outperformed the remaining scoring functions in the majority of instances. Additionally, a comparison of the orientation of the top ranked binding poses calculated using the fixed atomic charges of ligands obtained from force-field parameterization and by QM calculations in the protein environment provides strong evidence that the use of QM-derived charges is significant. [ABSTRACT FROM AUTHOR]

A computational procedure to search for selective ligands for structurally related protein targets was developed and verified for serotonergic 5-HT7/5-HT1A receptor ligands. Starting from a set of compounds with annotated activity at both targets (grouped into four classes according to their activity: selective toward each target, not-selective and not-selective but active) and with an additional set of decoys (prepared using DUD methodology), the SVM (Support Vector Machines) models were constructed using a selective subset as positive examples and four remaining classes as negative training examples. Based on these four component models, the consensus classifier was then constructed using a data fusion approach. The combination of two approaches of data representation (molecular fingerprints vs. structural interaction fingerprints), different training set sizes and selection of the best SVM component models for consensus model generation, were evaluated to determine the optimal settings for the developed algorithm. The results showed that consensus models with molecular fingerprints, a larger training set and the selection of component models based on MCC maximization provided the best predictive performance. [ABSTRACT FROM AUTHOR]

A series of 39 arylsulfonamide/amide derivatives of (aryloxy)ethyl alkyl amines, was designed with the support of the Virtual Combinatorial Library-Virtual Screening protocol, and synthesized using solid-phase methodologies. Representative compounds were biologically evaluated for their affinity for 5-HT 7 Rs and for their selectivity over related 5-HTRs (5-HT 1A Rs, 5-HT 2A Rs, 5-HT 6 Rs), dopamine D 2 Rs and adrenergic α 1 Rs. The study identified the derivatives 27 (3-fluoro-N-{1-[2-(2-cyclopentylphenoxy)ethyl]piperidin-4-yl}-benzenesulfonamide; PZ-1417) and 35 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide; PZ-1150) as being potent 5-HT 7 R antagonists with antidepressant and anxiolytic properties in the forced swim test (0.625–5 mg/kg and 0.625 mg/kg, respectively), the tail suspension test (0.625 mg/kg and 0.625 mg/kg, respectively), and in four plate test (0.625 mg/kg and 1.25–2.5 mg/kg, respectively) in mice. It has to be stressed that new compounds displayed higher activity than that of SB-269970, a reference 5-HT 7 R antagonist. Finally, the study provided valuable insight into the development of potential therapeutic agents for the treatment of CNS disorders. [ABSTRACT FROM AUTHOR]

The N -alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT 7 receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl- N -{1-[2-(2-( t -butyl)phenoxy)ethyl]piperidin-4-yl}- N -cyclopropylmethyl-1 H -pyrazole-4-sulfonamide), a potent and selective 5-HT 7 receptor antagonist and 33 (1-methyl- N -{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}- N -cyclopropylmethyl-1 H -pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT 2A /5-HT 7 /D 2 receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED = 1.25 mg/kg and 1 mg/kg, ip, respectively). These findings warrant further studies to explore the therapeutic potential of N -alkylated arylsulfonamides for the treatment of CNS disorders. [ABSTRACT FROM AUTHOR]

Virtual screening towards the search of new 5-HT 6 R ligands was carried out with three different fingerprints used for molecules representation. Two structurally new compounds were found to be characterized by a significant 5-HT 6 R activity ( K i of 119 and 670 nM). The compounds do not possess a positive ionizable group in their structures and therefore they belong to the group of atypical, non-basic 5-HT 6 R ligands. The obtained hits were proved to fit well in the 5-HT 6 R binding cavity by docking and molecular dynamic simulation experiments. Moreover, an in silico evaluation of the ADMET properties of these compounds predicted their drug-like character. [ABSTRACT FROM AUTHOR]

A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT 7 and 5-HT 1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT 7 receptors. Selected compounds 32 and 28 , which behaved as 5-HT 7 Rs antagonist and 5-HT 1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg ( 32 ) and 1.25 mg/kg ( 28 ). Compound 32 reduced immobility in a manner similar to the selective 5-HT 7 antagonist SB-269970. [ABSTRACT FROM AUTHOR]

Background: The paper presents a thorough analysis of the influence of the number of negative training examples on the performance of machine learning methods. Results: The impact of this rather neglected aspect of machine learning methods application was examined for sets containing a fixed number of positive and a varying number of negative examples randomly selected from the ZINC database. An increase in the ratio of positive to negative training instances was found to greatly influence most of the investigated evaluating parameters of ML methods in simulated virtual screening experiments. In a majority of cases, substantial increases in precision and MCC were observed in conjunction with some decreases in hit recall. The analysis of dynamics of those variations let us recommend an optimal composition of training data. The study was performed on several protein targets, 5 machine learning algorithms (SMO, Naïve Bayes, Ibk, J48 and Random Forest) and 2 types of molecular fingerprints (MACCS and CDK FP). The most effective classification was provided by the combination of CDK FP with SMO or Random Forest algorithms. The Naïve Bayes models appeared to be hardly sensitive to changes in the number of negative instances in the training set. Conclusions: In conclusion, the ratio of positive to negative training instances should be taken into account during the preparation of machine learning experiments, as it might significantly influence the performance of particular classifier. What is more, the optimization of negative training set size can be applied as a boosting-like approach in machine learning-based virtual screening. [ABSTRACT FROM AUTHOR]

Background: The paper presents a thorough analysis of the influence of the number of negative training examples on the performance of machine learning methods. Results: The impact of this rather neglected aspect of machine learning methods application was examined for sets containing a fixed number of positive and a varying number of negative examples randomly selected from the ZINC database. An increase in the ratio of positive to negative training instances was found to greatly influence most of the investigated evaluating parameters of ML methods in simulated virtual screening experiments. In a majority of cases, substantial increases in precision and MCC were observed in conjunction with some decreases in hit recall. The analysis of dynamics of those variations let us recommend an optimal composition of training data. The study was performed on several protein targets, 5 machine learning algorithms (SMO, Naïve Bayes, Ibk, J48 and Random Forest) and 2 types of molecular fingerprints (MACCS and CDK FP). The most effective classification was provided by the combination of CDK FP with SMO or Random Forest algorithms. The Naïve Bayes models appeared to be hardly sensitive to changes in the number of negative instances in the training set. Conclusions: In conclusion, the ratio of positive to negative training instances should be taken into account during the preparation of machine learning experiments, as it might significantly influence the performance of particular classifier. What is more, the optimization of negative training set size can be applied as a boosting-like approach in machine learning-based virtual screening. [ABSTRACT FROM AUTHOR]

A multidimensional analysis of machine learning methods performance in the classification of bioactive compounds was carried out. Eleven learning algorithms (including 4 meta-classifiers): J48, RandomForest, NaïveBayes, PART, Hyperpipes, SMO, Ibk, MultiBoostAB, Decorate, FilteredClassifier and Bagging, implemented in the WEKA package, were evaluated in the classification of 5 protein target ligands (cyclooxygenase-2, HIV-1 protease and metalloproteinase inhibitors, M1 and 5-HT1A agonists), using 8 different fingerprints for molecular representation (EStateFP, FP, ExtFP, GraphFP, KlekFP, MACCSFP, PubChemFP, and SubFP). The influence of the number of actives in the training data as well as the computational expenses expressed by the time required for building a predictive model was also taken into account. Tests were performed for sets containing a similar number of actives and inactives and also for datasets recreating virtual screening conditions. In order to facilitate the interpretation of results, the evaluating parameters (recall, precision, and MCC) values were presented in the form of heat maps. The classification of cyclooxygenase-2 inhibitors was almost perfect regardless of the conditions, yet the results for the rest of the targets varied between different experiments. The performance of machine learning methods was improved by increasing the number of actives in the training data; however, the moving to virtual screening conditions was generally connected with a significant fall in precision. Some methods, e.g. SMO, Bagging, Decorate and MultiBoostAB, were more stable regarding changes in classification conditions, whereas in the case of the others, such as NaïveBayes, J48 or Hyperpipes, the performance strongly varied between different datasets, fingerprints and targets. The application of meta-learning led to an increase in the values of evaluating parameters. KlekFP was a fingerprint which yielded the best results, although its use was connected with great computational expenses. On the other hand, EStateFP and SubFP gave worse results, especially in virtual screening-like conditions. [ABSTRACT FROM AUTHOR]

Background: A growing popularity of machine learning methods application in virtual screening, in both classification and regression tasks, can be observed in the past few years. However, their effectiveness is strongly dependent on many different factors. Results: In this study, the influence of the way of forming the set of inactives on the classification process was examined: random and diverse selection from the ZINC database, MDDR database and libraries generated according to the DUD methodology. All learning methods were tested in two modes: using one test set, the same for each method of inactive molecules generation and using test sets with inactives prepared in an analogous way as for training. The experiments were carried out for 5 different protein targets, 3 fingerprints for molecules representation and 7 classification algorithms with varying parameters. It appeared that the process of inactive set formation had a substantial impact on the machine learning methods performance. Conclusions: The level of chemical space limitation determined the ability of tested classifiers to select potentially active molecules in virtual screening tasks, as for example DUDs (widely applied in docking experiments) did not provide proper selection of active molecules from databases with diverse structures. The study clearly showed that inactive compounds forming training set should be representative to the highest possible extent for libraries that undergo screening. [ABSTRACT FROM AUTHOR]

Abstract: An analysis of the virtual combinatorial library was used for refining a pilot set of 34 derivatives and designing a targeted 38-member library of the arylamide and arylsulfonamide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines. All compounds 24–95 were synthesized according to an elaborated parallel solid-phase method and were biologically evaluated for their affinity for 5-HT7R. Additionally, the targeted library members were tested for 5-HT1A, 5-HT6, and D2 receptors. Selected compounds of particular interest were examined for their intrinsic activity at 5-HT7R in vitro employing a cAMP assay. The study allowed us to identify compound 68 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}piperidin-4-yl) benzenesulfonamide) as a potent 5-HT7R ligand (K i = 0.3 nM) with strong antagonistic properties (K b = 1 nM) and a 1450-fold selectivity over 5-HT1ARs. [Copyright &y& Elsevier]

Abstract: The two main groups of antidepressant drugs, the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs), as well as several other compounds, act by inhibiting the serotonin transporter (SERT). However, the binding mode and molecular mechanism of inhibition in SERT are not fully understood. In this study, five classes of SERT inhibitors were docked into an outward-facing SERT homology model using a new 4D ensemble docking protocol. Unlike other docking protocols, where protein flexibility is not considered or is highly dependent on the ligand structure, flexibility was here obtained by side chain sampling of the amino acids of the binding pocket using biased probability Monte Carlo (BPMC) prior to docking. This resulted in the generation of multiple binding pocket conformations that the ligands were docked into. The docking results showed that the inhibitors were stacked between the aromatic amino acids of the extracellular gate (Y176, F335) presumably preventing its closure. The inhibitors interacted with amino acids in both the putative substrate binding site and more extracellular regions of the protein. A general structure–docking-based pharmacophore model was generated to explain binding of all studied classes of SERT inhibitors. Docking of a test set of actives and decoys furthermore showed that the outward-facing ensemble SERT homology model consistently and selectively scored the majority of active compounds above decoys, which indicates its usefulness in virtual screening. [Copyright &y& Elsevier]

In the present study we have analyzed hydrogen bonding in dimer and trimer of oxalic acid, based on a recently proposed charge and energy decomposition scheme (ETS-NOCV). In the case of a dimer, two conformations, α and β, were considered. The deformation density contributions originating from NOCV's revealed that the formation of hydrogen bonding is associated with the electronic charge deformation in both the σ-(Δρ) and π-networks (Δρ). It was demonstrated that σ-donation is realized by electron transfer from the lone pair of oxygen on one monomer into the empty $$ \rho_{H - O}^* $$ orbital of the second oxalic acid fragment. In addition, a covalent contribution is observed by the density transfer from hydrogen of H-O group in one oxalic acid monomer to the oxygen atom of the second fragment. The resonance assisted component (Δρ), is based on the transfer of electron density from the π-orbital localized on the oxygen of OH on one oxalic acid monomer to the oxygen atom of the other fragment. ETS-NOCV allowed to conclude that the σ(O---HO) component is roughly eight times as important as π (RAHB) contribution in terms of energetic estimation. The electrostatic factor (ΔE) is equally as important as orbital interaction term (ΔE). Finally, comparing β-dimer of oxalic acid with trimer we found practically no difference concerning each of the O---HO bonds, neither qualitative nor quantitative. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: In an attempt to identify new ligands for the 5-HT7 receptor (5-HT7R), we developed and tested a hierarchical multi-step strategy of virtual screening (VS) based on two-dimensional (2D) pharmacophore similarity, physicochemical scalar descriptors, an ADME/Tox filter, three-dimensional (3D) pharmacophore searches and a docking protocol. Six chemical classes of 5-HT7R antagonists were used as query structures in a double-path virtual screening scheme. The Enamine screening database, consisting of approximately 730,000 commercially available drug-like compounds, was adopted and used as a source of structures. A biological evaluation of 26 finally selected virtual hits resulted in finding two benzodioxane derivatives with significant affinity (K i =197 and 265nM). The approach described in this case study can be easily used as a general rational drug design tool for other biological targets. [Copyright &y& Elsevier]

Abstract: A theoretical model is proposed for the crystal of β-oxalic acid, describing vibrational couplings between high- and low-frequency stretching modes in hydrogen bonds, resonance interactions between different hydrogen bonds in the unit cell, and Fermi resonance between the fundamental O–H(D) stretching and the overtone of the O–H(D) in-plane bending vibrations. The model is used for theoretical simulation of the O–H stretching bands of β-oxalic acid and its O–D derivative at 300K. The reproduction of the experimental bands is satisfactory. The presented model correctly fits the experimental line shape and fine structure. Also the effect of deuteration is well reproduced by this model. These results demonstrate that the proposed mechanisms are the principal ones for determining the dynamic interactions in H-bonded systems. Infrared spectra of β-oxalic acid and its deuterated derivative have been measured. Experimental geometry and frequencies are compared with the results of DFT and ab initio calculations performed at the B3LYP/6-31++G**, B3LYP/cc-pVTZ, B3PW91/6-31++G**, B3PW91/cc-pVTZ and MP2/6-31++G** levels. The calculated geometries and frequencies agree well with the experimental data. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • The fluorine substituent decreases the strength and frequency of N–H⋯N HBs. • The methodology to identify and separate individual HBs from the ab initio molecular dynamics trajectories. • The position of fluorine in the aromatic ring strongly affects the C–F bond length. • The number of N–H⋯F HBs is mainly dependent on the acidity of the proton of the NH 2 group. 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. [ABSTRACT FROM AUTHOR]

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 Ki values) and regression (where exact Ki value was predicted) experiments. [ABSTRACT FROM AUTHOR]

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 D4 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. [ABSTRACT FROM AUTHOR]

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. Image 1 • Serotonin receptor ligands with a unique activity profile have been synthesized. • The selected hit showed a dual 5-HT6/5-HT2A receptor activity. • Synthesized compound showed procognitive properties in vivo. [ABSTRACT FROM AUTHOR]

The complexes of selected long-chain arylpiperazines with homology models of 5-HT1A, 5-HT2A, and 5-HT7 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-HT1A and 5-HT2A 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-HT7 receptor, the third area of destabilization located at the extracellular end of the helix 6 was found. [ABSTRACT FROM AUTHOR]

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-HT1A, 5-HT2A, 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: Ki = 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. [ABSTRACT FROM AUTHOR]

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-HT1A, 5-HT6, 5-HT7, and dopamine D2 receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT1A and 5-HT7 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 (τ2) in synclinal conformation. Molecular docking studies indicate the role of halogen bonding in complexes of the most potent ligands and target receptors. [ABSTRACT FROM AUTHOR]

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-1 H -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 -(1 H -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)-1 H -indol-3-yl]-1 H -imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential. Image 1 • The first synthetic aminergic GPCR ligands built around the 2-aminoimidazole fragment. • Several differently functionalized 2-aminoimidazole based fragments tested. • Potent and very selective 5-HT 6 R antagonists revealed. • A significant conformational change occurs upon protonation of the amidine fragment. • Compound 9i (AHN-208) exhibited procognitive properties in NOR assay. [ABSTRACT FROM AUTHOR]

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 μ M, 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. [ABSTRACT FROM AUTHOR]

A conference paper is presented about cheminformatics hashed fingerprints density and its impact on machine learning methods performance. It informs that the machine learning methods are being applied in virtual screening (VS) to identify potentially active compounds out of large libraries of structures and emphasizes the importance of hashed fingerprinting generation in the process.

A conference paper about the influence of training actives or inactives ratio on machine learning performance is presented. It informs that the drug discovery, machine learning is widely used to classify molecules as active or inactive against a particular target. It further informs that the majority of these methods need a training set of objects to develop a decision rule.

A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HT 7 R antagonists. Among the compounds evaluated herein, 3-chloro- N -{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide ( 25 ) exhibited antagonistic properties at 5-HT 7 R and showed selectivity over selected serotoninergic and dopaminergic receptors, as well as over serotonin, noradrenaline and dopamine transporters. Compound 25 demonstrated significant antidepressant-like activity in the forced swim test (0.625–2.5 mg/kg, i . p .) and in the tail suspension test (1.25 mg/kg, i . p .), augmented the antidepressant effect of inactive doses of escitalopram (selective serotonin reuptake inhibitor) and bupropion (dopamine reuptake inhibitor) in the FST in mice, and similarly to SB-269970, exerted pro-cognitive properties in the novel object recognition task in cognitively unimpaired conditions in rats (0.3 mg/kg, i . p .). Such an extended pharmacological profile, especially the augmentation effect of the identified 5-HT 7 R antagonist on SSRI activity, seems promising regarding the complexity of affective disorders and potentially improved outcomes, including mnemonic performance. [ABSTRACT FROM AUTHOR]

As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3Kδ) 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. [ABSTRACT FROM AUTHOR]

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 1H-pyrrolo[3,2-c]quinoline on the quality of the salt bridge formed in the 5-HT6 receptor and D3 receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1H-pyrrolo[3,2-c]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HT6R affinity and more potent 5-HT6R antagonist properties when compared with the previously identified compound PZ-1643, a dual-acting 5-HT6R/D3R antagonist; nevertheless, the proposed modifications did not improve the activity at D3R. 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-HT6R binding site; however, they are unfavorable for such interactions at D3R. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • A novel framework for 5-HT 6 R ligands derived from 2-phenylpyrrole. • Exposure of the basic center is cricial to target different active states of 5-HT 6 R. • Compound 30 behaves as neutral antagonist at 5-HT 6 R-operated Gs signaling. • 5-HT 6 R neutral antagonists show cytoprotective effect in C8-D1A and human astrocytes. • Agonists and inverse agonists of 5-HT 6 R produce no cytoprotective effect. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: A 47-membered library of novel long-chain arylpiperazines, which contained cyclic amino acid amides in the terminal fragment (pyrrolidine-2-carboxamide and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide), was synthesized on Rink-amide resin and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Surprisingly, members of the designed series containing piperidine-2-carboxamide fragments underwent hydrolysis, which occurred during the acidic treatment for release from the solid-support, to their respective pipecolic acid analogs. Representative compounds from the library displayed high-to-low affinity for 5-HT7 (K i = 18–3134 nM) and 5-HT1A (K i = 0.5–6307 nM) sites. The possible interactions implicated in binding of the studied compounds to the 5-HT7 receptor were supported by molecular modeling. Research was also applied to support the exploration of the influence of the amide fragment, the length of alkylene spacer, and arylpiperazine substituents on the receptor's affinity and selectivity. [Copyright &y& Elsevier]

The varietal discrimination of honey is important because its bioactive properties, as well as specific characteristics, depend on the botanical origin. The present study aimed to verify the discriminatory power of Fourier-transform infrared spectroscopy (FT-IR) for differentiating Polish honeys and compare the results with the discrimination power of a model built on the basis of selected physicochemical parameters. For this purpose, buckwheat, rape, acacia, heather, goldenrod, and coniferous honeydew honeys were collected from trustworthy apiaries in different regions of Poland. The samples were further authenticated using pollen analysis and tested by means of FT-IR and the attenuated total reflection (ATR) technique. Basic psychochemical parameters were also assessed. The obtained data were analyzed by means of principal component analysis (PCA) and linear discriminant analysis (LDA). The obtained models were validated with a leave-one-out cross-validation (LOOCV) procedure. PCA analysis confirmed the usefulness of the ATR FT-IR method as a honey differentiation tool. The LDA for the FT-IR model allowed to correctly classify 26 out of 32 samples (81.3% accuracy), which was only slightly lower than for data the model based on the physiochemical characteristics (27 out of 32 samples and 84.4% accuracy), revealing a certain potential of FT-IR as fast evaluation method. • Discrimination power of FT-IR for differentiating Polish honeys was verified. • Important sources acacia, heather, goldenrod, and coniferous honeydew were tested. • The accuracy of an statistical model based on FT-IR spectra was 81.25%. • FT-IR statistic were better compared to models based on physicochemical data. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 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 D2 receptor antagonists with additional 5-HT6R 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-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R 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 D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis. [ABSTRACT FROM AUTHOR]

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. Image 1 • Multi-target directed ligands against Alzheimer's disease. • First dual-acting 5-HT 6 R inverse agonist at G s signaling/irreversible MAO-B inhibitor. • Glioprotective properties of 48 in 6-OHDA-induced toxicity. • Reversal of scopolamine-included memory deficits of 48 in the NOR test in rats. [ABSTRACT FROM AUTHOR]

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. Image 1 • Design and synthesis of 19 new (dichloro)phenyloxy derivatives of 1,3,5-triazine. • Radioligand binding assays for 5-HT 6 R target and 5-HT 2A R, 5-HT 7 R, D 2 R. • X-ray crystallography and molecular docking to 5-HT 6 R, including QPLD method. • Functional cAMP assays and drug-like profile in vitro. • Behavioral tests on procognitive effects (NOR and NOL) in vivo in rats. [ABSTRACT FROM AUTHOR]

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 ω1‐1a‐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 (~IC50 = 2 nM) than those of colchiceine (~IC50 = 6 μM). MDA‐MB‐231 breast cancer cell lines and human lung fibroblasts CCD39Lu were also tested. [ABSTRACT FROM AUTHOR]