Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors

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

Isomeric Activity Cliffs—A Case Study for Fluorine Substitution of Aminergic G Protein-Coupled Receptor Ligands

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

Spectroscopic and theoretical analysis of the effect of fluorine substitution on the strength of intermolecular hydrogen bonds.

Fluor jest najbardziej elektroujemnym pierwiastkiem występującymw naturze. Wprowadzenie go do cząsteczki determinuje wiele jejwłaściwości fizykochemicznych, takich jak: kwasowośćsąsiadujących grup funkcyjnych, zasadowość amin, biodostępność,lipofilowość, stabilność metaboliczną, itp. Obecnie, fluorowanieprojektowanych leków stało się standardową strategią mającą nacelu zwiększenie biodostępności oraz optymalizacji ich aktywnościbiologicznej. Od 1950 roku na rynek wprowadzono ponad 200fluorowanych leków, które obecnie stanowią około 20% wszystkichmedykamentów.Wiązania wodorowe są jednymi z najlepiej poznanych oddziaływańmiędzycząsteczkowych. Wpływają one na wiele różnychwłaściwości substancji chemicznych (np. temperaturę wrzenia czyprzewodnictwo roztworów), a także determinują budowę białek czyDNA. Jednak pomimo tak ogromnego znaczenia w przyrodzie, brakjest w literaturze systematycznych badań wpływu podstawnikafluorowego na siłę międzycząsteczkowych wiązań wodorowych.Najczęściej stosowaną metodą do badań wiązań wodorowych jestspektroskopia w podczerwieni, ponieważ ugrupowaniazaangażowane w tworzenie mostków wodorowych mają znaczącozmodyfikowane pasma.Celem pracy magisterskiej było zbadanie wpływu pozycjisubstytucji fluoru w pierścieniu aromatycznym na siłęmiędzycząsteczkowych wiązań wodorowych. by w przyszłościotrzymane rezultaty wykorzystać w racjonalnym projektowaniunowych leków.W niniejszej pracy wykorzystano różne metody badawcze (m.in.powierzchnie potencjału elektrostatycznego (ang. EPS),spektroskopię w podczerwieni FTIR, krystalografię rentgenowską(XRD) oraz dynamikę molekularną ab initio (ang. AIMD)), w celuwyjaśnienia wpływu substytucji fluoru na siłę wiązań wodorowychna przykładzie aniliny. Wybór modelowego układu wynikał z faktu,iż w ponad 50% fluorowanych leków podstawienie fluoremwystępowało bezpośrednio w pierścieniu aromatycznym.Badania wykazały, że wstawienie atomu fluoru do cząsteczki anilinyzmniejsza siłę międzycząsteczkowych wiązań wodorowych,szczególnie dla 3-fluoroaniliny, jednak sam fluor nie angażuje się wtworzenie mostków wodorowych. Analiza dynamiki molekularnejoraz struktur krystalicznych wykazała, że fluor w pozycji parazwiększa dostępność wolnej pary elektronowej na atomie azotu, coindukowało większą ilość powstających wiązań wodorowych.Otrzymane na podstawie dynamiki molekularnej widma teoretycznewykazały dużą zgodność z eksperymentem.Fluorine is the most electronegative element occurring in the nature.Introduction of fluorine atom to the molecule determines many of itsphysicochemical properties, i.e.: acidic character of neighbouringfunctional groups, basicity amines, bioavailability, lipophilicity,metabolic stability, etc. Nowadays, fluorination of drugs has becomea standard strategy to increase bioavailability and to optimisebiological activity. Since the 1950s, over 200 fluorine-containingdrugs have been released to the market which now makes up approx.20% of all pharmaceuticals.Hydrogen bonds are one of the best known intermolecularinteractions. They affect many properties of compounds such asboiling point and conductivity, but they also determine structure ofproteins and DNA. Infrared spectroscopy is the most commonly usedmethod to study the hydrogen bonding, whose presence significantlymodifies the bands involved in the formation of H-bonds. However,despite such great importance in nature, there is no systematic studyon the influence of fluoro substituent on the strength ofintermolecular hydrogen bonds. Infrared spectroscopy is the mostcommonly used method to study the hydrogen bonding, because thegroups involved in hydrogen bridge formation have significantlymodified bands.The aim of the thesis was to investigate the effect of fluorinesubstitution of the aromatic ring on the strength of the intermolecularH-bonds, to utilize the obtained results in the rational design of newdrugs.A broad range of methods were used (i.e.: electrostatic potentialsurface (EPS), FTIR infrared spectroscopy, X-ray crystallography(XRD) and ab initio molecular dynamics (AIMD)), to investigate theeffect of fluorine substitutions on the strength of hydrogen bondingin aniline. The choice of aniline as a model system stems from thefact that fluorinated aromatic ring is present in more than 50% offluorinated drugs.Results showed that the insertion of a fluorine atom into an anilinemolecule reduces the strength of intermolecular hydrogen bonds,particularly for 3-fluoroaniline, however, fluorine itself is not involved in H-bonds formation. Additional analysis of moleculardynamics and crystal structures showed that fluorine in the paraposition increases the availability of free electron pair of thenitrogen, which in consequence increases the number of H-bonds.Theoretical spectra obtained from the molecular dynamics showedhigh compatibility with the experimental data

Hydrogen Bonds with Fluorine in Ligand–Protein Complexes-the PDB Analysis and Energy Calculations

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”

Isomeric Activity Cliffs—A Case Study for Fluorine Substitution of Aminergic G Protein-Coupled Receptor Ligands

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

Tuning the Biological Activity of PI3K<i>δ</i> Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow

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