A DFT and ONIOM study of C–H hydroxylation catalyzed by nitrobenzene 1,2-dioxygenase

A detailed description of the mechanism of C–H hydroxylation by Rieske non-heme iron dioxygenases remains elusive, as the nature of the oxidizing species is not definitively known. DFT calculations on cluster models of nitrobenzene 1,2-dioxygenase were done to explore possible mechanisms arising from oxidation by either the experimentally observed FeIII–OOH complex or the putative high-valent HO–FeVQO intermediate formed through a heterolytic O–O bond cleavage. Hydrogen abstraction by HO–FeVQO, followed by oxygen rebound, was found to be consistent with experimental studies. The findings from the quantum mechanical cluster approach were verified by accounting for the effect of the protein environment on transition state geometries and reaction barriers through ONIOM calculations

Theoretical studies of energetics and binding isotope effects of binding a triazole-based inhibitor to HIV-1 reverse transcriptase

Understanding of protein-ligand interactions is crucial for rational drug design. Binding isotope effects, BIEs, can provide intimate details of specific interactions between individual atoms of an inhibitor and the binding pocket. We have applied multi-scale QM/MM simulations to evaluate binding energetics of a novel triazole-based non-nucleoside inhibitor of HIV-1 reverse transcriptase and to calculate associated BIEs. The binding sites can be distinguished based on the 18O-BIE.This work has been supported by the grants 2011/02/A ST4/00246 (Maestro) from the Polish National Research Center (NCN) and 0478/IP3/2015/73 (Iuventus Plus) from the Polish Ministry of Science and Higher Education

Triazole-Based Compound as a Candidate To Develop Novel Medicines To Treat Toxoplasmosis

This article reports anti-Toxoplasma gondii activity of 3-(thiophen-2-yl)-1,2,4-triazole-5-thione. The compound displayed significant and reproducible antiparasitic effects at nontoxic concentrations for the host cells, with an experimentally determined 50% inhibitory concentration (IC50) at least 30 times better than that of the known chemotherapeutic agent sulfadiazine. Purine nucleoside phosphorylase was defined as the probable target for anti-Toxoplasma activity of the tested compound. These results provide the foundation for future work to develop a new class of medicines to better treat toxoplasmosis

Influence of Association on Binding of Disaccharides to YKL-39 and hHyal-1 Enzymes

Disaccharide complexes have been shown experimentally to be useful for drug delivery or as an antifouling surface biofilm, and are promising drug-encapsulation and delivery candidates. Although such complexes are intended for medical applications, to date no studies at the molecular level have been devoted to the influence of complexation on the enzymatic decomposition of polysaccharides. A theoretical approach to this problem has been hampered by the lack of a suitable computational tool for binding such non-covalent complexes to enzymes. Herein, we combine quantum-mechanical calculations of disaccharides complexes with a nonstandard docking GaudiMM engine that can perform such a task. Our results on four different complexes show that they are mostly stabilized by electrostatic interactions and hydrogen bonds. This strong non-covalent stabilization demonstrates the studied complexes are some excellent candidates for self-assembly smart materials, useful for drug encapsulation and delivery. Their advantage lies also in their biocompatible and biodegradable character

1,4-disubstituted thiosemicarbazide derivatives are potent inhibitors of toxoplasma gondii proliferation.

A series of 4-arylthiosemicarbazides substituted at the N1 position with a 5-membered heteroaryl ring was synthesized and evaluated in vitro for T. gondii inhibition proliferation and host cell cytotoxicity. At non-toxic concentrations for the host cells all studied compounds displayed excellent anti-parasitic effects when compared to sulfadiazine, indicating a high selectivity of their anti-T. gondii activity. The differences in bioactivity investigated by DFT calculations suggest that the inhibitory activity of 4-arylthiosemicarbazides towards T. gondii proliferation is connected with the electronic structure of the molecule. Further, these compounds were tested as potential antibacterial agents. No growth-inhibiting effect on any of the test microorganisms was observed for all the compounds, even at high concentrations

Pharmacological and Structure-Activity Relationship Evaluation of 4-aryl-1-Diphenylacetyl(thio)semicarbazides

This article describes the synthesis of six 4-aryl-(thio)semicarbazides (series a and b) linked with diphenylacetyl moiety along with their pharmacological evaluation on the central nervous system in mice and computational studies, including conformational analysis and electrostatic properties. All thiosemicarbazides (series b) were found to exhibit strong antinociceptive activity in the behavioural model. Among them, compound 1-diphenylacetyl-4-(4-methylphenyl)thiosemicarbazide 1b was found to be the most potentan algesic agent, whose activity is connected with the opioid system. For compounds from series a significant anti-serotonergic effect, especially for compound 1-diphenylacetyl-4- (4-methoxyphenyl)semicarbazide 2b was observed. The computational studies strongly support the obtained results

Cytotoxic effect and molecular docking of 4-ethoxycarbonylmethyl-1-(piperidin-4-ylcarbonyl)-thiosemicarbazide—a novel topoisomerase II inhibitor

The preliminary cytotoxic effect of 4-ethoxycarbonylmethyl-1-(piperidin-4-ylcarbonyl)-thiosemicarbazide hydrochloride (1)—a potent topoisomerase II inhibitor—was measured using a MTT assay. It was found that the compound decreased the number of viable cells in both estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231breast cancer cells, with IC(50) values of 146 ± 2 and 132 ± 2 μM, respectively. To clarify the molecular basis of the inhibitory action of 1, molecular docking studies were carried out. The results suggest that 1 targets the ATP binding pocket. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00894-012-1679-6) contains supplementary material, which is available to authorized users

A DFT study of permanganate oxidation of toluene and its ortho -nitroderivatives

Calculations of alternative oxidationpathways of toluene and its ortho-substituted nitro derivatives by permanganate anion have been performed. The competition between methyl group and ring oxidation has been addressed. Acceptable results have been obtained using IEFPCM/B3LYP/6-31+G(d,p) calculations with zero-point (ZPC) and thermal corrections, as validated by comparison with the experimental data. It has been shown that ring oxidation reactions proceed via relatively early transition states that become quite unsymmetrical for reactions involving ortho-nitrosubstituted derivatives. Transition states for the hydrogen atom abstraction reactions, on the other hand, are late. All favored reactions are characterized by the Gibbs free energy of activation, ΔG≠, of about 25kcal mol−1. Methyl group oxidations are exothermic by about 20kcal mol−1 while ring oxidations are around thermoneutrality. Figure Oxidation of toluene and its ortho-nitroderivative

Mechanism of Cobalamin-Mediated Reductive Dehalogenation of Chloroethylenes

Reductive dehalogenation involving cobalamin has been proved to be a promising strategy for decontamination of the polluted environment. However, cob­(I)­alamin can act both as a strong reductant and a powerful nucleophile, and thus, several competing dehalogenation pathways may be involved. This work uses experimentally calibrated density functional theory on a realistic cobalamin model to resolve controversies of cobalamin-mediated reduction of chloroethylenes by exploring mechanisms of electron transfer, nucleophilic substitution, and nucleophilic addition. The computational results provide molecular-level insight into the competing pathways for chloroethylenes reacting with cob­(I)­alamin: the computed ratios of inner-sphere to outer-sphere pathways for perchloroethylene and trichloroethylene are 17:1 and 3.5:1, respectively, in accord with the corresponding experimental ratios of >10:1 and >2.3:1, while the computed outer-sphere pathway for other less-chlorinated ethylenes is hampered by high barriers (>25 kcal/mol). Thus, a new mechanistic picture has been obtained in which the highly chlorinated ethylenes primarily react via an inner-sphere nucleophilic-substitution pathway, whereas the less-chlorinated ethylenes mainly react through an inner-sphere nucleophilic-addition pathway. Especially, the quantitative comparison of standard reduction potentials between the formed chlorinated-cobalamin and cob­(II)­alamin/cob­(I)­alamin couple can be used to distinguish whether the inner-sphere pathway can proceed or not, and linear free-energy relationships have been developed to predict the reductive dehalogenation reactivity within a given mechanism. Finally, we propose new dual-isotope analyses for distinguishing the various environmental dehalogenation mechanisms

Multiple kinetic isotope effects of heavy-atoms

A discussion of the application of the rule of geometric mean to heavy atom kinetic isotope effect of reactions with complex mechanisms is presented. It is shown that the rule fails in the case of secondary heavy atom kinetic isotope effects