The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach

The mechanism-based inactivation (MBI) of P450 by paroxetine was investigated by computational analysis. The drug-enzyme interactions were figured out through studying energy profiles of three competing mechanisms. The potency of paroxetine as P450's inhibitor was estimated based on the availability of two active sites for the MBI in the paroxetine structure. The inactivation by the amino site of paroxetine mainly proceedsviathe hydrogen atom transfer pathway because of the lower energy demand of its rate determining step. In addition, the low-spin state is the predominant route in the MBI at the methylenedioxo active site as a result of being rebound barrier-free mechanism. Our comparative investigation showed that inactivation at the secondary amine is thermodynamically more favorable because of the lower energy barrier of the dehydration mechanism of the hydroxylated paroxetine complex than its methylenedioxo counterpart. The results of docking analysis coincided with the outputs of DFT calculations since the docking pose with the lowest binding affinity is that for conformation with polar interaction between the amino group of paroxetine and the oxo moiety of P450's active site. Assessment of the molecular dynamics simulations trajectories revealed the favorable interaction of paroxetine with P450This work has DGI Projects No. CTQ2015-63997-C

Perturbating intramolecular hydrogen bonds through substituent effects or non-covalent interactions

An analysis of the effects induced by F, Cl, and Br-substituents at the α-position of both, the hydroxyl or the amino group for a series of amino-alcohols, HOCH2(CH2)nCH2NH2 (n = 0–5) on the strength and characteristics of their OH···N or NH···O intramolecular hydrogen bonds (IMHBs) was carried out through the use of high-level G4 ab initio calculations. For the parent unsubstituted amino-alcohols, it is found that the strength of the OH···N IMHB goes through a maximum for n = 2, as revealed by the use of appropriate isodesmic reactions, natural bond orbital (NBO) analysis and atoms in molecules (AIM), and non-covalent interaction (NCI) procedures. The corresponding infrared (IR) spectra also reflect the same trends. When the α-position to the hydroxyl group is substituted by halogen atoms, the OH···N IMHB significantly reinforces following the trend H 2(CH2)nCH2NH2 (n = 0–3) interact with BeF2. Although the presence of the beryllium derivative dramatically increases the strength of the IMHBs, the possibility for the beryllium atom to interact simultaneously with the O and the N atoms of the amino-alcohol leads to the global minimum of the potential energy surface, with the result that the IMHBs are replaced by two beryllium bonds

Ionization, intrinsic basicity, and intrinsic acidity of unsaturated diols of astrochemical interest: 1,1- and 1,2-ethenediol: A theoretical survey

The structure, stability, and bonding characteristics of 1,1- and 1,2-ethenediol, their radical cations, and their protonated and deprotonated species were investigated using high-level ab initio G4 calculations. The electron density of all the neutral and charged systems investigated was analyzed using the QTAIM, ELF, and NBO approaches. The vertical ionization potential (IP) of the five stable tautomers of 1,2-ethenediol and the two stable tautomers of 1,1-ethenediol go from 11.81 to 12.27 eV, whereas the adiabatic ones go from 11.00 to 11.72 eV. The adiabatic ionization leads to a significant charge delocalization along the O-C-C-O skeleton. The most stable protonated form of (Z)-1,2-ethenediol can be reached by the protonation of both the anti-anti and the syn-anti conformers, whereas the most stable deprotonated form arises only from the syn-anti one. Both charged species are extra-stabilized by the formation of an O-H O intramolecular hydrogen bond (IHB) which is not found in the neutral system. (Z)-1,2-ethenediol is predicted to be less stable, less basic, and more acidic than its cis-glycolaldehyde isomer. The most stable protonated species of (E)-1,2-ethenediol comes from its syn-syn conformer, although the anti-anti conformer is the most basic one. Contrarily, the three conformers yield a common deprotonated species, so their acidity follows exactly their relative stability. Again, the (E)-1,2-ethenediol is predicted to be less stable, less basic, and more acidic than its trans-glycolaldehyde isomer. Neither the neutral nor the protonated or the deprotonated forms of 1,1-ethenediol show the formation of any O-H O IHB. The most stable protonated species is formed by the protonation of any of the two tautomers, but the most stable deprotonated form arises exclusively from the syn-anti neutral conformer. The conformers of 1,1-ethenediol are much less stable and significantly less basic than their isomer, acetic acid, and only slightly more acidicThis work was carried out with financial support from the projects PID2021-125207NB-C31 and PID2019-110091GB-I00 of the Ministerio de Ciencia, Innovacion y Universidades of Spain (MICINN) and the project Y2020/EMT-6290 (PRIES-CM) of the Comunidad de Madri

A theoretical survey of the UV–visible spectra of axially and peripherally substituted boron subphthalocyanines

The UV–visible spectra of a series of subphthalocyanines (SubPcs) characterized by three different axial substituents (An ) in combination with H, F, NO2, SO2 H and SO2 CH3 peripheral substituents (Ri ) were predicted and analyzed by means of time-dependent DFT calculations, including chloroform as a solvent. In this analysis, we paid particular attention to the Q band, which remained almost unchanged regardless of the nature of the axial substituent. For the same axial substituent, changes in the Q band were also rather small when hydrogens at the periphery were replaced by R1 = SO2 H and R1 = R2 = SO2 H. However, the shifting of the Q band was almost 10 times larger when R1 = NO2 and R1 = R2 = NO2 due to the participation of this substituent in the π SubPc cloud. In most cases, the characteristics of the spectra can be explained considering only the transitions involving the HOMO-1, HOMO, LUMO and LUMO + 1 orbitals, where the Q band can be decomposed into two main contributions, leading to charge separation. Only for SubPc(A3,F,F,H) would one of the two contributions from the deepest orbital involved not lead to charge transfer. For this latter case, the HOMO-2 orbital must also be taken into account. In summary, the results obtained with the analysis of the MO indicate that the studied SubPcs are appropriate for photochemical device

Unimolecular reactivity upon collision of uracil-Ca2+ complexes in the gas phase: Comparison with uracil-M+ (M = H, alkali metals) and uracil-M2+ (M = Cu, Pb) systems

International audienc

Heparin-like disaccharides: effect of metallic complexation in fragmentation pathways as characterized by MS/MS and UVPD experiments

Communication par afficheNational audienc

A COMBINED EXPERIMENTAL AND DFT INVESTIGATION OF ISOMERIC HEPARIN DISACCHARIDES METAL COMPLEXES

Communication par afficheHeparin (HP) glycosaminoglycans (GAGs) 1 , an anticoagulant drug, are recognized to be a biologically important polysaccharide, and have been involved in many biological processes such as blood coagulation, cell-cell and cell-matrix interaction inflammatory processes, cell growth, lipid transport and metabolism.  Why is it important to study the interaction between HP and metal cations? The effect of metal ions on protein-carbohydrate complexes is largely unknown. Heparin-biomolecule interaction can be influenced by the binding of metal ions to these complexes 2. For example, it has been reported that physiological Ca 2+ induces conformational changes in heparin that are necessary for the interaction between the anticoagulant Heparin and Annexin V, a protein proposed to play an important role in the inhibition of blood coagulation 3. It is therefore a Calcium-dependant interaction.  What is our strategy? Experimentally our aim was to study (Ca(II-H)) + and (Ca(II-A)) + complexes by tandem ESI/MS. Once generated in the gas phase, ions then undergo a fragmentation process by Collision Induced Dissociation (CID). The Ca 2+ cation induces different conformational changes in both isomers, resulting in completely different fragmentation pathways. Theoretically our aim is to explain this Metal-HP interaction by DFT calculations and delineate mechanisms of dissociation accounting for the experimental data.  Why II-A and II-H isomers? Without metal there is no difference in the MS/MS spectra of these two isomers. Only 0,2 A 2 fragmentation is observed. With Ca 2+ dissociation pattern changes drastically. Interaction between Acetyl/Ca 2+ must be important in the dissociation process. O O COOH HO OH O OH OH NH 2 OSO 3 O O COOH HO OH O OH OH NHAc OSO 3 0,2 A 2 * 0,2 X 1 * II-H II-A MS/MS results: Experiments were carried out on a LTQ Orbitrap XL mass spectrometer coupled to an ESI source. Nitrogen gas was used as collision gas. Computational results: The geometries were optimized using the density functional theory (DFT) with the B3LYP hybrid functional and 6-311G** basis set. Refined relative energies were obtained at the 6-311++G(3df,2p) level. Without Ca 2+ all the calculated 50 conformers, for each disaccharide, are very close in energy (50KJ/mol). High Binding Energy (BE) values (~1400 KJ/mol) are obtained. As deduced from the conformers calculation and the BE values, the metal complex stabilizes strongly one structure. It seems safe to deduce that both sugars lose partially their possibilities to change structurally. Biologically, this consideration could be critical in order to explain the strong interactions aforementioned. Analytically, when (Ca(HP)) + is formed, the molecule loses it flexibility due to the fixation structure effect and therefore it is noticed a decrease in the number of fragments. Leary et al. 4 delineates mechanisms of dissociation for isomeric HP without metal based upon CID experiments and H/D exchange. Another mechanism has been tested in this work but those pathways remain the most favorable ones.  0,2 A 2 Dissociation The acetyl group in II-A blocks the R1 (Rearrangement) step. Nevertheless, it is still possible to transfer the proton through the acetyl carbonyl group. The energy associated (PT2 barrier) is however bigger (163 KJ/mol) than for II-H (-55 KJ/mol).  0,2 X 1 Dissociation Starting from the initial structures, and using the dissociation mechanism given by Leary et al. shown below, the same methodology will be employed in order to unravel the 0,2 X 1 fragmentation pattern. , Ca 2

Reactivity of alloxydim herbicide: force and reaction electronic flux profiles

The reaction force profle and the electronic reaction fux concepts were explored for the herbicide alloxydim and some of its derivatives at B3LYP/6-311G(d,p) level of theory. The exploration was achieved by rotating the oxime bond which is the most reactive region of the molecule. The main objective is to understand how the rotation of this bond infuences the properties of the molecule and induces an electronic reorganization. The results show that the rotation of the dihedral angle triggers alloxydim to go through three transition states. The frst step of the transformation begins by the rupture of the hydrogen bond and is characterized by a pronounced structural reorganization. In the last step of the process the electronic reorganization is more importantThe work presented was funded by project PID2019-110091GB-I00 and PDC2021-121203-I00 of the Ministerio de Ciencia, Innovación of Spain and by the project Y2020/ EMT-6290 (PRIES-CM) of the Comunidad de Madrid, Spai

The Acidity of a Carbon Nucleophile Dictates Enantioselectivity and Reactivity in Michael Additions to Aromatic and Aliphatic Enals via Iminium Activation

The Michael addition of activated methylenes to β-substituted α,β-unsaturated aldehydes (enals) via iminium catalysis takes place following reactivity and enantioselectivity patterns which depend on the electronic nature of the substituent in the β position (β-aryl or β-alkyl). Application of the same reaction conditions to both families of enals may result in erratic levels of asymmetric induction in the reactions of β-aryl enals or low reactivity with β-alkyl enals. A systematic analysis of this behavior using phenylacetic acid derivatives as case studies has led us to find a general trend: the different problems found for β-aryl and β-alkyl enals depend on the acidity of the nucleophile, and the outcome of the reaction for both types of enals can be improved substantially by careful choice of catalyst, solvent, and additive. Furthermore, this study has allowed us to understand subtle aspects of this transformation and has enabled the formulation of a general and reliable protocol to obtain high yields and enantioselectivities consistently, regardless of the acidity of the nucleophile and the nature of the substituent (aromatic or aliphatic) at the β positionWe thank CTQ-2009-12168, CAM (AVANCAT CS2009/PPQ-1634), UAM-CAM (CCG10-UAM/PPQ-5769), CTQ-2012-35957, CTQ2015-63997-C2-1-P, CTQ2016-78779-R and FOTOCARBON-CAM S2013/MIT-2841 for financial support. S.D. thanks the Comunidad Autónoma de Madrid (CAM), and E.R. and S.M. thank MICINN, for predoctoral fellowships. P.M. thanks MICINN for a Ramón y Cajal contract and the EU for a Marie Curie grant (CIG: HYPERCAT-30422

Rumex dentatus L. phenolics ameliorate hyperglycemia by modulating hepatic key enzymes of carbohydrate metabolism, oxidative stress and PPARγ in diabetic rats

Rumex dentatus L. is a flowering plant with promising therapeutic effects. This study investigated the antioxidant efficacy of phenolic compounds isolated from R. dentatus L. in vitro and by conducting density function theory (DFT) studies to explore the mechanisms of action. The antioxidant, anti-inflammatory and antidiabetic effects of polyphenols-rich R. dentatus extract (RDE) were investigated in type 2 diabetic rats. Phytochemical investigation of the aerial parts of R. dentatus resulted in the isolation of one new and seven known compounds isolated for the first time from this species. All isolated phenolics showed in vitro radical scavenging activity. The antioxidant activity of the compounds could be oriented by the hydrogen atom transfer and sequential proton loss electron transfer mechanisms in gas and water phases, respectively. In diabetic rats, RDE attenuated hyperglycemia, insulin resistance and liver injury and improved carbohydrate metabolism. RDE suppressed oxidative stress and inflammation and upregulated PPARγ. In silico molecular docking analysis revealed the binding affinity of the isolated compounds toward PPARγ. In conclusion, the computational calculations were correlated with the in vitro antioxidant activity of R. dentatus derived phenolics. R. dentatus attenuated hyperglycemia, liver injury, inflammation and oxidative stress, improved carbohydrate metabolism and upregulated PPARγ in diabetic ratsThis work has DGI Project no. CTQ2015-63997-C2, a generous allocation of computing time at the Centro de Computación Científica of the UAM is also acknowledge