Acidifying Effect of an N-Oxide Group – A Useful Motif in Enhancing Acidity towards Superacidic Values

DFT calculations carried out on trans-decahydronaphthalene and 4b,8b-dihydronaphthalene, important structural features of many alkaloids, revealed that they are moderately acidic carbon acids in the gas-phase and in DMSO solution. Substitution with a nitrogen atom of a neighbouring C(sp3)–H fragment bonded to an acidic centre reduces the corresponding acidity in both phases. Following that, oxidation of the nitrogen atom to an N–oxide group enhances the acidity significantly. This acidifying effect of an N–oxide moiety in the vicinity of a deprotonation centre was estimated to be around 9−17 kcal mol-1 in the gas-phase deprotonation enthalpy and about 5−11 pKa units in DMSO. Therefore, this electronic effect could be applied in the design of novel strong acids and superacids. Such acidity enhancement is identified through triadic analysis to be a consequence of the final state effect of anion, where compounds bearing an N–oxide group benefit from the favourable charge-dipole interaction between the negative charge and an N–O group. A dramatic increase in acidity is observed upon multiple cyanation. For example, octacyanoquinolizine N–oxide is an extremely strong superacid as seen by the gas-phase ΔHacid = 254.8 kcal mol-1 and pKa,DMSO = −20.2, and its synthesis is highly desirable and strongly recommended. Triadic analysis suggests that this huge acidifying effect takes place because of strong resonance in anions of polycyano compounds, efficiently assisted by multiple CN groups, which stabilizes the corresponding principal molecular orbitals

The Use of Multiscale Molecular Simulations in Understanding a Relationship between the Structure and Function of Biological Systems of the Brain: The Application to Monoamine Oxidase Enzymes

Computational techniques provide accurate descriptions of the structure and dynamics of biological systems, contributing to their understanding at an atomic level.Classical MD simulations are a precious computational tool for the processes where no chemical reactions take place.QM calculations provide valuable information about the enzyme activity, being able to distinguish among several mechanistic pathways, provided a carefully selected cluster model of the enzyme is considered.Multiscale QM/MM simulation is the method of choice for the computational treatment of enzyme reactions offering quantitative agreement with experimentally determined reaction parameters.Molecular simulation provide insight into the mechanism of both the catalytic activity and inhibition of monoamine oxidases, thus aiding in the rational design of their inhibitors that are all employed and antidepressants and antiparkinsonian drugs. Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological, and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors, and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM, and QM/MM approaches to probe the chemical mechanisms of enzymatic activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed

Ring Strain and Other Factors Governing the Basicity of Nitrogen Heterocycles – An Interpretation by Triadic Analysis

M06–2X/6–311++G(2df,2pd)//M06–2X/6–31+G(d) computations were employed to investigate the intrinsic gas phase basicity of strained nitrogen heterocycles involving aziridine, azetidine, pyrrolidine and piperidine, together with their N-methyl and N-phenyl derivatives, NR(CH2)n (n = 2–5; R = H, Me and Ph). Basicity constants were compared with the corresponding acyclic counterparts, NR(CH3)2 (R = H, Me and Ph), and were, based on triadic analysis, resolved into contributions mirroring features of both initial base and the final protonated form as well as their interplay, thus offering quantitative insight into the obtained results. In general, the N-methyl derivatives provided strongest bases investigated here, and, within each group of molecules, the basicity increased on going from three- to six-membered rings, con-sistent with a decrease in ring strain, with four-membered systems already surpassing or coming close to the basicity of the acyclic gauge molecule. Calculated basicities were found in a very good agreement with available experimental data, except for N–methylazetidine, where a remarkable discrepancy was revealed, suggesting that this system should be experimentally reassessed and its gas-phase basicity parameters revised. Triadic analysis showed different behaviour of individual contributions governing basicities, both among and within distinct families of molecules. It also convincingly demonstrated that, if a proper and a quantitatively accurate interpretation of observed basicity trends is desired, one should not rely only on concepts such as localized reactive hybrid orbitals (RHO) or thus derived nitrogen electron-donating ability (T. Ohwada et al., J. Org. Chem. 69 (2004) 7486), which take into account only properties of the initial base in question, but rather consider protonation reaction in its entirety. (doi: 10.5562/cca2121

Hydrogen Bond Dynamics of Histamine Monocation in Aqueous Solu-tion: How Geometric Parameters Influence the Hydrogen Bond Strength

Chemometric statistical approaches involving multiple linear regression (MLR) and principal compo-nent analysis (PCA) were employed on a set of 42 distinct snapshot structures of the physiological histamine monocation in aqueous solution along the Car-Parrinello molecular dynamics trajectory, in order to obtain a better insight into the relationship between the geometry parameters of the system and the resulting νNH stretching frequencies. A simple 2D linear regression of νNH with Namino•••Owater distances gave a very poor correlation (R2 = 0.42), but both MLR and PCA with the inclusion of four directly bonded water molecules offered a notably predictive model that is even able to distinguish two classes of structures based on the Cl– counterion position. Taking into account waters from the first, second and third solvation shells, sequentially diminished the overall predictive ability of the model, yet increased the number of useful predictors that, in the largest model with 51 solvent mole-cules, all correspond to bulk water, implying that both chemometric methods are consistent in suggest-ing that fundamental histamine N–H stretching vibrations are very complex in nature and strongly coupled to the fluctuating environ-ment

Indomethacin increases quercetin affinity for human serum albumin: a combined experimental and computational study and its broader implications

Human serum albumin (HSA) is the most abundant carrier protein in human body. Competition for the same binding site between different ligands can lead to an increased active concentration or a faster elimination of one or both ligands. Indomethacin and quercetin both bind to the binding site located in the IIA subdomain. To determine the nature of HSA-indomethacin- quercetin interactions, spectrofluorometric, docking, molecular dynamics studies, and quantum chemical calculations were performed. Results show that indomethacin and quercetin binding sites do not overlap. Moreover, the presence of quercetin does not influence the binding constant and position of indomethacin in the pocket. However, binding of quercetin is much more favorable in the presence of indomethacin, with its position and interactions with HSA significantly changed. These results provide a new insight into drug-drug interactions, which can be important in situations when displacement from HSA or other proteins is undesirable or even desirable. This principle could also be used to deliberately prolong or shorten xenobiotics’ half-life in the body, depending on the desired outcomes