Hydrogen Bond Acceptor Strength Research Articles

Paradoxical Increase of Permeability and Lipophilicity with the Increasing Topological Polar Surface Area within a Series of PRMT5 Inhibitors.

An imidazolone → triazolone replacement addressed the limited passive permeability of a series of protein arginine methyl transferase 5 (PRMT5) inhibitors. This increase in passive permeability was unexpected given the increase in the hydrogen bond acceptor (HBA) count and topological polar surface area (TPSA), two descriptors that are typically inversely correlated with permeability. Quantum mechanics (QM) calculations revealed that this unusual effect was due to an electronically driven disconnect between TPSA and 3D-PSA, which manifests in a reduction in overall HBA strength as indicated by the HBA moment descriptor from COSMO-RS (conductor-like screening model for real solvation). HBA moment was subsequently deployed as a design parameter leading to the discovery of inhibitors with not only improved passive permeability but also reduced P-glycoprotein (P-gp) transport. Our case study suggests that hidden polarity as quantified by TPSA-3DPSA can be rationally designed through QM calculations.

Balance Between Contact and Solvent-Separated Ion Pairs in Mixtures of the Protic Ionic Liquid [Et3NH][MeSO3] with Water Controlled by Water Content and Temperature

The formation of aggregates of ionic species is a crucial process in liquids and solutions. Ion speciation is particularly interesting for the case of ionic liquids (ILs) since these Coulombic fluids consist solely of ions. Most of their unique properties, such as enthalpies of vaporization and conductivities, are strongly related to ion pair formation. Here, we show that the balance of hydrogen-bonded contact ion pairs (CIP) and solvent-separated (SIP) ion pairs in protic ionic liquids (PILs) and in their mixtures with water can be well understood by a combination of far-infrared (FIR) and mid-infrared (MIR) spectroscopy, density functional theory (DFT) calculations of PIL/water aggregates, and molecular dynamics (MD) simulations of PIL/water mixtures. This combined approach is applied to mixtures of triethylammonium methanesulfonate [Et3NH][MeSO3] with water. It is shown that ion speciation in this mixture depends on three parameters: the relative hydrogen bond acceptor strength of the counter ion and the molecular solvent, the solvent concentration, and the temperature. For selected PIL/water mixtures, the equilibrium constants for CIPs and SIPs were determined as a function of the solvent content and temperature. Finally, for the studied PIL/water mixtures, the transition from CIPs to SIPs could be understood on enthalpic and entropic grounds. A detailed picture of this interconversion process could be described at the molecular level by means of MD simulations. In addition, the concentration dependence of ion pair formation can be well understood with help of a simplified "cartoon-like" statistical model describing hydrogen bond redistribution.

A computational study of hydrogen bonding motifs in halide, tetrafluoroborate, hexafluorophosphate, and tetraarylborate salts of chiral cationic ruthenium and cobalt guanidinobenzimidazole hydrogen bond donor catalysts; acceptor properties of the “BArf” anion

The chiral complexes [(η5-C5H5)Ru(CO)(GBI)]+ X− and mer-[Co(GBI)3]3+ 3X−, where GBI is the chelate ligand 2-guanidinobenzimidazole (HN=C(NHH′)NHC(NHR)=NR′), are effective hydrogen bond donor catalysts for a variety of organic reactions. Salts with X− = halide, BF4−, PF6− and BArf− (B(3,5-C6H3(CF3)2)4−) are studied computationally as an initial step in rationalizing reactivity trends and enantioselectivities. A variety of cation/anion hydrogen bonding motifs are identified, some involving a dyad of synperiplanar NH linkages (HN=C(NHH′)NHC(NHR)=NR′), and others (more stable) involving a triad (HN=C(NHH′)NHC(NHR)=NR′). Within each series, the gas phase ΔG values follow the order Cl− (most negative ΔG) < BF4−< PF6− < BArf−, paralleling catalytic activities and (inversely) hydrogen bond acceptor strengths suggested experimentally. With BF4−, all hydrogen bonds involve F-B-F units; with PF6−, both cis-F-P-F and mer-F-PF-F units can bind; with BArf− the isomers feature 2–6 NH⋯FC− and 1–2 NH⋯π interactions. The ΔG values in CH2Cl2 show a few differences in relative stabilities, which are analyzed; in the ruthenium series, free or solvent separated ions are predicted to be the major species for all PF6− and BArf− salts. Crystallographically characterized BArf− salts where the cations possess NH donor groups are analyzed.

Synthesis, antimicrobial and antioxidant evaluation, and molecular docking study of 4,5-disubstituted 1,2,4-triazole-3-thiones

There is a growing need for new antibiotics and antifungal drugs to combat pathogenic bacteria and fungi. In order to develop potential antimicrobial agents, some 1,2,4-triazole-3-thiones were synthesized from the reaction of hydrazides with isothiocyanates under optimized conditions in deep eutectic solvent of potassium carbonate-glycerol (1:5 M ratio). Blocking properties of all products were assessed on a variety of Gram-positive and Gram-negative bacterial as well as fungal pathogens. Good to excellent inhibitory effects especially against fungi were observed with all synthesized compounds. 5-(4-Hydroxyphenyl)-4-(4-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (3b) showed significant antioxidant activity according to the results obtained from 2,2-diphenyl-1-picrylhydrazylf (DPPH) free radical scavenging experiments. The possible interaction mechanism of synthetic triazoles with 1IYL enzyme on Aspergillus fumigatus was investigated by molecular docking method. A complete agreement was found between experimental data and theoretical calculations. Hydrogen bond acceptor strength of N-1 in 1,2,4-triazole rings was the main cause of the observed differences.

Machine learning models for hydrogen bond donor and acceptor strengths using large and diverse training data generated by first-principles interaction free energies

We present machine learning (ML) models for hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD) strengths. Quantum chemical (QC) free energies in solution for 1:1 hydrogen-bonded complex formation to the reference molecules 4-fluorophenol and acetone serve as our target values. Our acceptor and donor databases are the largest on record with 4426 and 1036 data points, respectively. After scanning over radial atomic descriptors and ML methods, our final trained HBA and HBD ML models achieve RMSEs of 3.8 kJ mol−1 (acceptors), and 2.3 kJ mol−1 (donors) on experimental test sets, respectively. This performance is comparable with previous models that are trained on experimental hydrogen bonding free energies, indicating that molecular QC data can serve as substitute for experiment. The potential ramifications thereof could lead to a full replacement of wetlab chemistry for HBA/HBD strength determination by QC. As a possible chemical application of our ML models, we highlight our predicted HBA and HBD strengths as possible descriptors in two case studies on trends in intramolecular hydrogen bonding.

Crystal structures and FT-IR spectra of three N,N-dicyclohexylmethylammonium halides C13H26N+ X − (X = Cl, Br, I)

Abstract The title compounds C13H26N+Cl− (N,N-dicyclohexylmethylammonium chloride), C13H26N+Br− (N,N- dicyclohexylmethylammonium bromide) and C13H26N+I− (N,N-dicyclohexylmethylammonium iodide) are isostructural and crystallize in the orthorhombic space group Pna21 with the lattice parameters a=7.580(1), b=19.072(1), c=9.165(1) Å, V=1324.9(1) Å3 for X=Cl, a=7.765(1), b=19.054(1), c=9.270(1) Å, V=1371.5(1) Å3 for X=Br, and a=8.102(1), b=19.084(1), c=9.535(1) Å, V=1474.2(1) Å3 for X=I with Z=4 for each compound. Their cyclohexyl groups are aligned along [010] while their halide ions are coordinated along [100] by a strong linear N–H···X (X=Cl, Br, I) hydrogen bond. Fourier-transform infrared spectra show a decreasing hydrogen bond acceptor strength from the chloride to the iodide.

Gaussian Process Regression Models for the Prediction of Hydrogen Bond Acceptor Strengths.

We present two approaches for the computation of hydrogen bond acceptor strengths, one by machine-learning and one by a composite quantum-mechanical protocol, both based on the well-established pKBHX scale and dataset. The QM calculations after a necessary linear fit reproduce the complexation free energies in solution with an RMSE of 2.6 kJ mol-1 , not far off the expected error of 2 kJ mol-1 obtained from the comparison of experimental data from two different sources. The second approach is by Gaussian Process Regression (GPR) machine-learning. We describe the hydrogen bond acceptor atoms by a radial atomic reactivity descriptor that encodes their electronic and steric environment. The performance of the GPR model on an external test set corresponds to 3.3 kJ mol-1 , which is also close to the experimental error. We apply the GPR model built on experimental data to model the hydrogen bond acceptor strengths of a series of hydrogen bond acceptor sites of 10 phosphodiesterase 10 A inhibitors. The predicted values correlate well with the experimentally measured IC50 values.

Structure-Property Basis for Solving Transporter-Mediated Efflux and Pan-Genotypic Inhibition in HCV NS5B Inhibitors.

In solving the P-gp and BCRP transporter-mediated efflux issue in a series of benzofuran-derived pan-genotypic palm site inhibitors of the hepatitis C virus NS5B replicase, it was found that close attention to physicochemical properties was essential. In these compounds, where both molecular weight (MW >579) and TPSA (>110 Å2) were high, attenuation of polar surface area together with weakening of hydrogen bond acceptor strength of the molecule provided a higher intrinsic membrane permeability and more desirable Caco-2 parameters, as demonstrated by trifluoroacetamide 11 and the benchmark N-ethylamino analog 12. In addition, the tendency of these inhibitors to form intramolecular hydrogen bonds potentially contributes favorably to the improved membrane permeability and absorption. The functional group minimization that resolved the efflux problem simultaneously maintained potent inhibitory activity toward a gt-2 HCV replicon due to a switching of the role of substituents in interacting with the Gln414 binding pocket, as observed in gt-2a NS5B/inhibitor complex cocrystal structures, thus increasing the efficiency of the optimization. Noteworthy, a novel intermolecular S=O···C=O n → π* type interaction between the ligand sulfonamide oxygen atom and the carbonyl moiety of the side chain of Gln414 was observed. The insights from these structure-property studies and crystallography information provided a direction for optimization in a campaign to identify second generation pan-genotypic NS5B inhibitors.

Solvent Basicity, A Study of Kamlet–Taft β and Gutmann DN Values Using Computationally Derived Molecular Properties

Solvent basicity is recognized as playing a major role in solvation and is included, through empirical basicity parameters, in linear free energy relationships that account for the effects of changes in solvent on chemical reactions. It is reasonable to postulate that the basicity of a solvent molecule reflects some combination of its molecular properties. In the present study, density functional calculations using the B3LYP functional, and Hartree–Fock calculations have been used to calculate the partial atomic charges (using the Hirshfeld and CM5 models), orbital energies, polarizabilities, dipole moments and quadrupolar amplitudes for over one hundred molecules for which there are experimental values for two basicity parameters, Kamlet and Taft’s hydrogen bond acceptor strength, β, and Gutmann’s donor number, DN, a measure of Lewis basicity. Regression of the experimental β and DN values against molecular descriptors reflecting the above molecular properties yields a remarkably consistent picture. For both parameters the values for alcohols and amines lie systematically off of the regression lines through the remaining compounds, which include alkanes, aromatics, halogenated alkanes and aromatics, esters, carbonates, carboxylic acids, ketones, ethers, nitriles, phosphates, sulfides and sulfates. Independent of the calculation method or method of estimating the partial atomic charges, both experimental β and DN are essentially determined by two molecular properties: the charge on the most negative atom of the molecule and the molecular orbital from which charge donation would occur. The regression results using any of the fours sets of descriptors (reflecting the two calculation methods and two methods of charge estimation) are remarkably similar for β and DN supporting the view that these are measures of the same “basicity”.

Hybridization of Nitrogen Determines Hydrogen-Bond Acceptor Strength: Gas-Phase Comparison of Redshifts and Equilibrium Constants.

Gas-phase Fourier transform infrared spectroscopy and quantum chemical calculations are combined to illustrate the effect of hybridization on the hydrogen-bond acceptor strength of nitrogen by a comparison of nine bimolecular complexes. We present gas-phase results for the complexes of methanol, ethanol, and 2,2,2-trifluoroethanol with acetonitrile (sp-hybridized N) and find that the structure of these complexes is nearly linear and dominated by the OH···N hydrogen bond with no experimental indication of an OH-π bonded structure. We compare experimental redshifts and equilibrium constants, obtained by combining experiments and theory, for these complexes to the corresponding complexes with pyridine (sp2-hybridized N) and trimethylamine (sp3-hybridized N). The comparison clearly illustrates that increasing the s-character of the nitrogen lone pair decreases the hydrogen-bond acceptor strength (sp3 > sp2 > sp). The observed trend correlates with the basicity of the acceptors and can be explained by the partial charge on the accepting nitrogen atom and the degree of localization of the nitrogen lone pair.

Halocarbons as hydrogen bond acceptors: a spectroscopic study of haloethylbenzenes (PhCH2CH2X, X = F, Cl, Br) and their hydrate clusters.

The electronic spectra of 2-bromoethylbenzene and its chloro and fluoro analogues have been recorded by resonant two-photon ionisation (R2PI) spectroscopy. Anti and gauche conformers have been assigned by rotational band contour analysis and IR-UV ion depletion spectroscopy in the CH region. Hydrate clusters of the anti conformers have also been observed, allowing the role of halocarbons as hydrogen bond acceptors to be examined in this context. The donor OH stretch of water bound to chlorine is red-shifted by 36 cm-1, or 39 cm-1 in the case of bromine. Although classed as weak H-bond acceptors, halocarbons are favourable acceptor sites compared to π systems. Fluorine stands out as the weakest H-bond acceptor amongst the halogens. Chlorine and bromine are also weak H-bond acceptors, but allow for more geometric lability, facilitating complimentary secondary interactions within the host molecule. Ab initio and DFT quantum chemical calculations, both harmonic and anharmonic, aid the structural assignments and analysis.

Prediction of the equivalent alkane carbon number (EACN) of aprotic polar oils with COSMO-RS sigma-moments

The Equivalent Alkane Carbon Numbers (EACNs) of 16 aprotic polar hydrocarbon oils are measured by the fish-tail method. These values, supplemented by 54 already reported EACNs of other hydrocarbon oils are used, as a training set, to build up a QSPR model, based on COSMO-RS σ-moments as oil descriptors. It provides a reliable model requiring only three meaningful molecular parameters i.e. the surface area (M0oil), the overall polarity (M2oil) and the hydrogen bond acceptor strength (Maccoil) of the oil. The robustness of this predictive model is verified with a validation set including various polar oils such as esters, ketones, acetates or nitriles. Furthermore the model is also valid to predict EACN values of weakly polar oils, such as, (cyclo)alkenes, terpenes, aromatics, alkynes and chloroalkanes, as well as bifunctional compounds, namely ethyl oleate, terpenic acetates, dialkyldiethers and hexylmethacrylate.

Phospholipid bilayer affinities and solvation characteristics by electrokinetic chromatography with a nanodisc pseudostationary phase.

Phospholipid bilayer nanodiscs composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and synthetic maleic acid-styrene copolymer belts have been introduced as a pseudostationary phase (PSP) in electrokinetic chromatography and demonstrated good performance. The nanodiscs provide a suitable migration range and high theoretical plate counts. Using this nanodisc pseudostationary phase, the affinity of the bilayer structure for probe solutes was determined and characterized. Good correlation is observed between retention factors and octanol water partition coefficients for particular categories of solutes, but the general correlation is weak primarily because the nanodiscs show stronger affinity than octanol for hydrogen bond donors. This suggests that a more appropriate application of this technology is to measure and characterize interactions between solutes and lipid bilayers directly. Linear solvation energy relationship analysis of the nanodisc-solute interactions in this study demonstrates that the nanodiscs provide a solvation environment with low cohesivity and weak hydrogen bond donating ability, and provide relatively strong hydrogen bond acceptor strength.

Modulating the strength of hydrogen bond acceptors to achieve low Caco2 efflux for oral bioavailability of PARP inhibitors blocking centrosome clustering

During the lead generation and optimization of PARP inhibitors blocking centrosome clustering, it was discovered that increasing hydrogen bond acceptor (HBA) strength improved cellular potency but led to elevated Caco2 and MDR1 efflux and thus poor oral bioavailability. Conversely, compounds with lower efflux had reduced potency. The project team was able to improve the bioavailability by reducing efflux through systematic modifications to the strength of the HBA by changing the electronic properties of neighboring groups, whilst maintaining sufficient acceptor strength for potency. Additionally, it was observed that enantiomers with different potency showed similar efflux, which is consistent with the promiscuity of efflux transporters. Eventually, a balance between potency and low efflux was achieved for a set of lead compounds with good bioavailability which allowed the project to progress towards establishing in vivo pharmacokinetic/pharmacodynamic relationships.

Quantum mechanical estimation of Abraham hydrogen bond parameters using 1:1 donor-acceptor complexes

Hydrogen bond donor strength () and acceptor strength () have been successfully used in models of many environmental and chemical systems, and a number of computational methods have been developed to predict them. In this work, a quantum chemical Moller–Plesset perturbation (MP2) method is applied to estimate the binding free energies (ΔGhbond) of several 1:1 hydrogen-bonded complexes. A correlation between the binding free energies and hydrogen bond strength is established. This relationship can be used to develop an accurate computational model for predicting and using binding free energies. The accuracy of the method in predicting Abraham (root mean squared deviation (RMSD) = 0.0693) and (RMSD = 0.0677) are comparable to the empirical, fragment-based ABSOLV method (RMSD = 0.1144 and 0.1281 for and , respectively). The binding free energy has been decomposed into its thermodynamic components, and it is demonstrated that the linear relationships in the dataset and the existence of magic point can be attributed to a constant entropy of reaction. Copyright © 2014 John Wiley & Sons, Ltd.

2-Deuterated Histidine is a Raman Reporter of Histidine's Protonation State, Hydrogen Bonding, and Metal Coordination

The C-2 proton on the imidazole side chain of the amino acid Histidine (His) can be isotopically exchanged for deuterium under mild reaction conditions, thus creating a unique C-D stretching band that can serve as a site-specific reporter of the environment and role of specific His residues in proteins. This band is a very weak infrared band but is clearly visible in nonresonant Raman spectra. His residues can participate in a number of different interactions unique to the His imidazole ring. Model compound work has shown that the peak frequency and spectral properties of this novel C-D vibrational band is dependent on imidazole protonation state, hydrogen bond donor and acceptor strength, and metal coordination, while salt bridge dependence in the model protein T4 lysozyme is currently being studied. Based on protein work that confirms the model compound protonation dependence, larger and more complex protein systems with multiple, distinct His residues, like superoxide dismutase, are currently targeted to report the environment and interactions of multiple specific His residues within the same protein.

Studies of molecular modeling on drug design of Listeria monocytogenes internalin B β-sheet

Internalin B (InlB) is an extracellular virulence factor of the bacterium Listeria monocytogenes , (italic) and it contains seven leucine rich repeats (LRRs) which is composed of seven β-strands aligned to form a continuous β–sheet. This β–sheet which is composed of a linear arrangement of five exposed aromatic amino acids is a hot–spot for host receptor (Met) binding and this is the goal of our studies. At first glance, the molecule were optimized with 6 to 31G (d,p) basis set in the gas phase at the Hartree–Fock (HF) level of theory. To simulate the solvent effect, the HF optimized parameters were used as initial input for subsequent HF/self–consistent reaction field (SCRF) calculations in a variety of solvents which represent a wide range of solvent properties from the point of view of polarity, as well as the hydrogen bond donor and acceptor strength, implementing 6 to 31G (d,p) atomic basis set. For deeper investigations of β–sheet folding, thermodynamic signatures of this biomolecule as an island of cooperatively–ordered hydrogen–bonded network by calculating Gibbs free energy and enthalpy were determined. Four different temperatures that this bacterium may encounter in the environment, and in cold-blooded animals or warm-blooded hosts in three solvent media were used. Then, NMR studies was carried out on the basis of gauge-including atomic orbital (GIAO) method at HF/6–31G (d,p) level of theory, to gain more insight to solvent effects on aromatic amino acids 15 N and 17 O atoms shielding in order to probe InlB–Met (ligand–protein) binding via clarifying of chemical shift mapping and dynamics. Key words : Internalin B, β–sheet (un) folding, thermodynamics, solvent effect, nuclear magnetic resonance.

Oxadiazole isomers: all bioisosteres are not created equal

Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compounds were evaluated and found to have significant differences in their various physical and pharmaceutical properties. Experimental and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects.

Miscibility of Ionic Liquids with Polyhydric Alcohols

Liquid-liquid miscibility temperatures as a function of composition have been determined experimentally for the binary systems formed by ionic liquids ([bmim][BF(4)], [bmim][PF(6)], [emim][Tf(2)N], [bmim][Tf(2)N], [hmim][Tf(2)N]) and polyhydric alcohols (1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2,3-propanetriol, 1,2-butanediol). The impact of ionic liquid and di- or three-hydroxy alcohol characteristics focusing on the effect of the IL's anion nature, cation alkyl chain length, and alcohol structure (number of hydroxyl groups, position of the hydroxy groups in the molecule, and number of carbon atoms in the diols) is presented. It appears that all systems exhibit upper critical solution temperatures. For dihydroxy alcohols mentioned above, miscibility with 1-butyl-3-methylimidazolium ionic liquids follows the order [BF(4)](-) > [Tf(2)N](-) > [PF(6)](-) and is dependent on the hydrogen-bond basicity of the anion. Analysis of these findings leads us to conclude that the miscibility of ionic liquids is likely related to the hydrogen-bond acceptor strength of the anion. Comparing the miscibility of 1,2-ethanediol with 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imides, it can be seen that surprisingly, T(c)([emim](+)) < T(c)([bmim](+)) < T(c)([hmim](+)). This arrangement of critical temperatures is opposite to that observed earlier for systems with monohydroxy alcohols. Analyzing the influence of the polyhydroxy alcohol structure, we also noticed that the miscibility of the polyhydroxy alcohols with [bmim][Tf(2)N] or [bmim][BF(4)] decreases when the polarity of the alcohol rises.

Prediction of the Intrinsic Hydrogen Bond Acceptor Strength of Chemical Substances from Molecular Structure

Hydrogen bonding affects the partitioning of organic compounds between environmental and biological compartments as well as the three-dimensional shape of macromolecules. Using the semiempirical quantum chemical AM1 level of calculation, we have developed a model to predict the site-specific hydrogen bond (HB) acceptor strength from ground-state properties of the individual compounds. At present, the model parametrization is confined to compounds with one HB acceptor site of the following atom types: N, O, S, F, Cl, and Br that act as lone-pair HB acceptors, and pi-electron (aromatic or conjugated) systems with the associated C atoms as particularly weak HB acceptors. The HB acceptor strength is expressed in terms of the Abraham parameter B and calculated from local molecular parameters, taking into account electrostatic, polarizability, and charge transfer contributions according to the Morokuma concept. For a data set of 383 compounds, the squared correlation coefficient r2 is 0.97 when electrostatic potential (ESP) derived net atomic charges are employed, and the root-mean-square (rms) error is 0.04 that is in the range of experimental uncertainty. The model is validated using an extended leave-50%-out approach, and its performance is comparatively analyzed with the ones of earlier introduced ab initio (HF/6-31G**) and density functional theory (B3LYP/6-31G**) models as well as of two increment methods with respect to the total compound set as well as HB acceptor type subsets. The discussion includes an explorative model application to amides and organophosphates that demonstrates the robustness of the approach, and further opportunities for model extensions.