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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]

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]

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". [ABSTRACT FROM AUTHOR]

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]

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. [Display omitted] • Fluorine-halogen substitution increase activity of SERT ligands. • Halogens interact through a hybrid halogen-hydrogen bonds. • XSAR methodology identified the best halogen substitution pattern. [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]

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α, β, γ, δ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3Kδ, displaying IC50 values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC50 value of 18 nM for PI3Kδ), good selectivity (for PI3Kδ relative to other PI3K isoforms: PI3Kα/δ = 79; PI3Kβ/δ = 1415; PI3Kγ/δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment. [ABSTRACT FROM AUTHOR]

Among all of the monoaminergic receptors, the 5-HT 6 R has the highest number of non-basic ligands (approximately 5% of compounds stored in 25th version of ChEMBL database have the strongest basic pKa below 5, calculated using the Instant JChem calculator plugin). These compounds, when devoid of a basic nitrogen, exhibit high affinity and remarkable selectivity. Despite a decade of research, no clues have been given for explanation of such an intriguing phenomenon. Here, a series of analogs of four known 5-HT 6 R ligands, has been rationally designed to approach this issue. For each of the synthesized 42 compounds, a binding affinity for 5-HT 6 R has been measured, together with a selectivity profile against 5-HT 1A R, 5-HT 2A R, 5-HT 7 R and D 2 R. Performed induced fit docking and molecular dynamics experiments revealed that no particular interaction was responsible for the activity of non-basic compounds. In fact, a plain N -phenylsulfonylindole (1e) was found to possess a moderate (5-HT 6 R, K i = 159 nM) affinity. No other monoaminergic receptor has as simple and selective ligand as this one. Thus, it is stated that it binds to the receptor solely based on its conformation and as such, possesses a minimum amount of features, required for binding. Also, any functional group able to form an additional interaction with the receptor increase the binding affinity, like in the case of two highly active non-basic compounds 3e and 5g (5-HT 6 R, K i = 65 nM and 38 nM, respectively). Image 1 • The analysis of activity of non-basic serotonin receptor ligands is performed. • Substantially simplified ligands still exhibit affinity for the receptor. • N-Phenylsulfonyl indole possess all features necessary for the activity. • A slight, weak interaction increases the baseline activity. • A new pharmacophore for 5-HT6R is proposed. [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]

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 (h ERG) channel by introducing fluorine atoms in a group of 1 H -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 h ERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1 H -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. [Display omitted] • Fluorine atoms in diminishing the undesirable h ERG affinity. • Six water molecules important for MAO-B inhibitor binding based on MD simulations. • Glioprotective properties of selective reversible MAO-B inhibitors. • Procognitive properties of selective reversible MAO-B inhibitor 26 in NOR test. • Antidepressant-like activity of reversible MAO-B inhibitor 26 in FST. [ABSTRACT FROM AUTHOR]

The colchicine (1:1) complexes with monovalent cations: Li+, Na+ and K+ as well as divalent cation Mg2+ of nitrate salts were synthesized and characterized by 1H and 13C NMR, FT-IR, UV–Vis, ESI-MS, spectroscopic methods and elemental analysis. In the ESI-MS mass spectra (in ES+ mode) formation of complexes of different stoichiometry 1:1, 2:1, 3:1, (colchicine – metal cation) was detected and in complexation process nitrate anions are also involved. Stoichiometry 1:1:1, 1:2:1, 2:1:1 and 2:2:1 (colchicine – metal cation – nitrate anion) of colchicine complexes with nitrate salts were also detected. The structures of the colchicine complexes with Li+, Na+, K+ and Mg2+ cations are discussed in details by PM5 semiempirical calculations, DFT, M06-2X theoretical calculations, molecular dynamics (MD) simulations and molecular modelling. Complexes were also screened against fungicidal and cytotoxic activity. The antifungal activity of colchicine and all complexes was assayed in vitro against eight fungi species. Cytotoxic activity of all complexes was tested against ovarian cancer cell SKOV-3 line. The colchicine (1:1) complexes with monovalent cations: Li+, Na+ and K+ as well as divalent cation Mg2+ of nitrate salts were synthesized and characterized by 1H and 13C NMR, FT-IR, UV–Vis, ESI-MS, spectroscopic methods and elemental analysis. The structures of the colchicine complexes with Li+, Na+, K+ and Mg2+ cations are discussed in details by PM5 semiempirical calculations, M06-2X theoretical calculations, molecular dynamics (MD) simulations and molecular modelling. Complexes were also screened against fungicidal and cytotoxic activity. Image 1 [ABSTRACT FROM AUTHOR]