Methemoglobinemia caused by 8-aminoquinoline drugs: DFT calculations suggest an analogy to H4B's role in nitric oxide synthase.
Ontology highlight
ABSTRACT:
SUBMITTER: Liu H
PROVIDER: S-EPMC3070186 | biostudies-literature | 2011 Feb
REPOSITORIES: biostudies-literature
Publications
Methemoglobinemia caused by 8-aminoquinoline drugs: DFT calculations suggest an analogy to H4B's role in nitric oxide synthase.
Liu Haining H Walker Larry A LA Nanayakkara N P Dhammika NP Doerksen Robert J RJ
Journal of the American Chemical Society 20110118 5
We suggest a possible mechanism of how 8-aminoquinolines (8-AQ's) cause hemotoxicity by oxidizing hemoglobin to methemoglobin. In our DFT calculations, we found that 5-hydroxyprimaquine is able to donate an electron to O(2) to facilitate its conversion to H(2)O(2). Meanwhile, Fe(II) is oxidized to Fe(III) and methemoglobin is formed. In this mechanism, the 8-AQ drug plays a similar role as that of H(4)B in nitric oxide synthase. Furthermore, our study offers an approach to inform the design of l ...[more]
Similar Datasets
Project description:Nitric oxide is produced in Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus by the bacterial isoform of nitric oxide synthase (NOS). Inhibition of bacterial nitric oxide synthase (bNOS) has been identified as a promising antibacterial strategy for targeting methicillin-resistant S. aureus [Holden, J. K., et al. (2015) Chem. Biol. 22, 785-779]. One class of NOS inhibitors that demonstrates antimicrobial efficacy utilizes an aminoquinoline scaffold. Here we report on a variety of aminoquinolines that target the bacterial NOS active site, in part, by binding to a hydrophobic patch that is unique to bNOS. Through mutagenesis and crystallographic studies, our findings demonstrate that aminoquinolines are an excellent scaffold for further aiding in the development of bNOS specific inhibitors.
| S-EPMC5283056 | biostudies-literature
Project description:Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic l-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability.
| S-EPMC3954451 | biostudies-literature
Project description:Nitrobenzene poisoning is uncommon, with most cases occurring in the dye, paint, and other chemical industries. Nitrobenzene enters the body mainly through the skin, respiratory tract, and oral cavity. Nitrobenzene poisoning symptoms include hypermethemoglobinemia, hemolytic anemia, liver and kidney dysfunction, cardiogenic pulmonary edema, and toxic encephalopathy, which endanger people's lives. Therefore, we present a case of nitrobenzene poisoning caused by skin absorption, focusing on its clinical characteristics and treatment outcomes. A 58 years-old man presented to our department with confusion and cyanosis. He has a history of hypertension and cerebral infarction. The patient was diagnosed with moderate occupational acute benzene poisoning with nitro compounds. Symptomatic support, methylene blue, and other antioxidant treatments were commenced after diagnosis. After treatment, the patient's condition gradually improved, and he was discharged.
| S-EPMC9988939 | biostudies-literature
Project description:The cleavage of covalent C-H bonds is one of the most energetically demanding, yet biologically essential, chemical transformations. Two C-H bond cleavages are involved in the reaction catalyzed by thymidylate synthase (TSase), which provides the sole de novo source of thymidylate (i.e., the DNA base T) for most organisms. Our QM/MM free energy calculations show that the C-H ? O proton transfer has three transition states that are energetically similar but structurally diverse. These characteristics are different from our previous calculation results on the C-H ? C hydride transfer, providing an explanation for differences in temperature dependences of KIEs on these two C-H bond activation steps. The calculations also suggest that the traditionally proposed covalent bond between the protein and substrate (the C6-S bond) is very labile during the multistep catalytic reaction. Collective protein motions not only assist cleavage of the C6-S bond to stabilize the transition state of the proton transfer step but also rearrange the H-bond network at the end of this step to prepare the active site for subsequent chemical steps. These computational results illustrate functionalities of specific protein residues that reconcile many previous experimental observations and provide guidance for future experiments to examine the proposed mechanisms. The synchronized conformational changes in the protein and ligands observed in our simulations demonstrate participation of protein motions in the reaction coordinate of enzymatic reactions. Our computational findings suggest the existence of new reaction intermediates not covalently bound to TSase, which may lead to a new class of drugs targeting DNA biosynthesis.
| S-EPMC3634118 | biostudies-literature
Project description:Flavo-diiron proteins (FDPs) are widespread in anaerobic bacteria, archaea, and protozoa, where they serve as the terminal components of dioxygen and nitric oxide reductive scavenging pathways. FDPs contain an N,O-ligated diiron site adjacent to a flavin mononucleotide (FMN) cofactor. The diiron site is structurally similar to those in hemerythrin, ribonucleotide reductase, and methane monooxygenase. However, only FDPs turn over NO to N2O at significant rates and yields. Previous studies revealed sequential binding of two NO molecules to the diferrous site, forming mono- and dinitrosyl intermediates leading to N2O formation. In the present work, these mono- and dinitrosyl intermediates have been characterized by EPR and Mössbauer spectroscopies and DFT calculations. Our results show that the iron proximal to the cofactor binds the first NO to form the diiron mononitrosyl complex, implying the iron distal to the FMN binds the second NO to form the diiron dinitrosyl intermediate. The exchange-coupling constants, J (H = JS1·S2), were found to differ substantially, +17 cm-1 for the diiron mononitrosyl and +60 cm-1 for the diiron dinitrosyl. Notwithstanding this large difference, our findings indicate retention of at least one hydroxo bridge throughout the NOR catalytic cycle. The Mossbauer hyperfine parameters and DFT calculations confirmed a semibridging NO- ligand in the mononitrosyl intermediate that lowers the exchange parameter. The DFT calculations on the dinitrosyl intermediate suggest a contribution to J from direct exchange between the S = 1 spins on the NO- ligands, which could initiate N-N bond formation. Our results provide insight into why FDPs are the only known nonheme diiron enzymes that competently turn over NO to N2O.
| S-EPMC6602092 | biostudies-literature
Project description:Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole > Oxfendazole > Nocodazole > Mebendazole > Albendazole > Oxibendazole > Fenbendazole > Ciclobendazole > Thiabendazole > Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate.
| S-EPMC8024586 | biostudies-literature
Project description:Objective. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is often present in diabetic (DB) patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH. Methods. Adult male diabetic (BKS.Cg-Dock7m +/+ Leprdb /J) (db/db) mice (10 weeks old) and their heterozygote littermates were subjected to CIH or intermittent air (IA) for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic), IH (intermittent hypoxia nondiabetic), IADB (intermittent air diabetic), and IHDB (intermittent hypoxia diabetic) groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO) were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6), and asymmetric dimethylarginine (ADMA) were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE) staining. Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group. Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.
| S-EPMC5093285 | biostudies-other
Project description:The nitric oxide synthase (NOS) enzyme consists of multiple domains connected by flexible random coil tethers. In a catalytic cycle, the NOS domains move within the limits determined by the length and flexibility of the interdomain tethers and form docking complexes with each other. This process represents a key component of the electron transport from the flavin adenine dinucleotide/reduced nicotinamide adenine dinucleotide phosphate binding domain to the catalytic heme centers located in the oxygenase domain. Studying the conformational behavior of NOS is therefore imperative for a full understanding of the overall catalytic mechanism. In this work, we have investigated the equilibrium positional distributions of the NOS domains and the bound calmodulin (CaM) by using Monte Carlo calculations of the NOS conformations. As a main experimental reference, we have used the magnetic dipole interaction between a bifunctional spin label attached to T34C/S38C mutant CaM and the NOS heme centers, which was measured by pulsed electron paramagnetic resonance. In general, the calculations of the conformational distributions allow one to determine the range and statistics of positions occupied by the tethered protein domains, assess the crowding effect of the multiple domains on each other, evaluate the accessibility of various potential domain docking sites, and estimate the interaction energies required to achieve target populations of the docked states. In the particular application described here, we have established the specific mechanisms by which the bound CaM facilitates the flavin mononucleotide (FMN)/heme interdomain docking in NOS. We have also shown that the intersubunit FMN/heme domain docking and electron transfer in the homodimeric NOS protein are dictated by the existing structural makeup of the protein. Finally, from comparison of the calculated and experimental docking probabilities, the characteristic stabilization energies for the CaM/heme domain and the FMN domain/heme domain docking complexes have been estimated as -4.5kT and -10.5kT, respectively.
| S-EPMC7534783 | biostudies-literature
Project description:We investigate the effect of relativity on harmonic vibrational frequencies. Density functional theory (DFT) calculations using the four-component Dirac-Coulomb Hamiltonian have been performed for 15 hydrides (H2X, X = O, S, Se, Te, Po; XH3, X = N, P, As, Sb, Bi; and XH4, X = C, Si, Ge, Sn, Pb) as well as for HC≡CPbH3. The vibrational frequencies have been calculated using finite differences of the molecular energy with respect to geometrical distortions of the nuclei. The influences of the choice of basis set, exchange-correlation functional, and step length for the numerical differentiation on the calculated harmonic vibrational frequencies have been tested, and the method has been found to be numerically robust. Relativistic effects are noticeable for the heavier congeners H2Te and H2Po, SbH3 and BiH3, and SnH4 and PbH4 and are much more pronounced for the vibrational modes with higher frequencies. Spin-orbit effects constitute a very small fraction of the total relativistic effects, except for H2Te and H2Po. For HC≡CPbH3 we find that only the frequencies of the modes with large contributions from Pb displacements are significantly affected by relativity.
| S-EPMC8667032 | biostudies-literature
Project description:On a comprehensive database with 1,644 datapoints, covering several aspects of main-group as well as of transition metal chemistry, we assess the performance of 60 density functional approximations (DFA), among them 36 double hybrids (DH). All calculations are performed using a Slater type orbital (STO) basis set of triple-ζ (TZ) quality and the highly efficient pair atomic resolution of the identity approach for the exchange- and Coulomb-term of the KS matrix (PARI-K and PARI-J, respectively) and for the evaluation of the MP2 energy correction (PARI-MP2). Employing the quadratic scaling SOS-AO-PARI-MP2 algorithm, DHs based on the spin-opposite-scaled (SOS) MP2 approximation are benchmarked against a database of large molecules. We evaluate the accuracy of STO/PARI calculations for B3LYP as well as for the DH B2GP-PLYP and show that the combined basis set and PARI-error is comparable to the one obtained using the well-known def2-TZVPP Gaussian-type basis set in conjunction with global density fitting. While quadruple-ζ (QZ) calculations are currently not feasible for PARI-MP2 due to numerical issues, we show that, on the TZ level, Jacob's ladder for classifying DFAs is reproduced. However, while the best DHs are more accurate than the best hybrids, the improvements are less pronounced than the ones commonly found on the QZ level. For conformers of organic molecules and noncovalent interactions where very high accuracy is required for qualitatively correct results, DHs provide only small improvements over hybrids, while they still excel in thermochemistry, kinetics, transition metal chemistry and the description of strained organic systems.
| S-EPMC7317772 | biostudies-literature