A Study Modeling Bridged Nucleic Acid-Based ASOs and Their Impact on the Structure and Stability of ASO/RNA Duplexes.

Antisense medications treat diseases that cannot be treated using traditional pharmacological technologies. Nucleotide monomers of bare and phosphorothioate (PS)-modified LNA, N-MeO-amino-BNA, 2',4'-BNANC[NH], 2',4'-BNANC[NMe], and N-Me-aminooxy-BNA antisense modifications were considered for a detailed DFT-based quantum chemical study to estimate their molecular-level structural and electronic properties. Oligomer hybrid duplex stability is described by performing an elaborate MD simulation study by incorporating the PS-LNA and PS-BNA antisense modifications onto 14-mer ASO/RNA hybrid gapmer type duplexes targeting protein PTEN mRNA nucleic acid sequence (5'-CTTAGCACTGGCCT-3'/3'-GAAUCGUGACCGGA-5'). Replica sets of MD simulations were performed accounting to two data sets, each set simulated for 1 µs simulation time. Bulk properties of oligomers are regulated by the chemical properties of their monomers. As such, the primary goal of this work focused on establishing an organized connection between the monomeric BNA nucleotide's electronic effects observed in DFT studies and the macroscopic behavior of the BNA antisense oligomers, as observed in MD simulations. The results from this study predicted that spatial orientation of MO-isosurfaces of the BNA nucleotides are concentrated in the nucleobase region. These BNA nucleotides may become less accessible for various electronic interactions when coupled as ASOs forming duplexes with target RNAs and when the ASO/RNA duplexes further bind with the RNase H. Understanding such electronic interactions is crucial to design superior antisense modifications with specific electronic properties. Also, for the particular nucleic acid sequence solvation of the duplexes although were higher compared to the natural oligonucleotides, their binding energies being relatively lower may lead to decreased antisense activity compared to existing analogs such as the LNAs and MOEs. Fine tuning these BNAs to obtain superior binding affinity is thus a necessity.

Computational Approach to Unravel the Role of Hydrogen Bonding in the Interaction of NAMI-A with DNA Nucleobases and Nucleotides.

Density functional theory method in combination with a continuum solvation model is used to understand the role of hydrogen bonding in the interactions of tertiary nitrogen centers of guanine and adenine with monoaqua and diaqua NAMI-A. In the case of adenine, the interaction of N3 with monoaqua NAMI-A is preferred over that of N7 and N1 whereas, N7 site is the most preferred site over N3 and N1 in the diaqua ruthenium-adenine interaction. In the monoaqua and diaqua NAMI-A-guanine interactions, the N7 site is the most preferred site over the N3 site. Here, the strength and number of H-bonds play important roles in stabilizing intermediates and transition states involved in the interaction of NAMI-A and purine bases. Atoms in molecules and Becke surface analysis confirm that the interactions between monoaqua and diaqua NAMI-A with the base pairs of GC and AT dinucleotides leads to the structural deformation in the geometry of the base pairs of dinucleotides. The diaqua NAMI-A adducts induce more disruption in the base pairs as compared to monoaqua NAMI-A adducts. which suggests that diaqua NAMI-A could be a better anticancer agent than monoaqua NAMI-A. This study can be extended to envisage the potential applications of computational studies in the development of new drugs and targeted drug delivery systems.

Fenton's Reagent Catalyzed Release of Carbon Monooxide from 1,3-Dihydroxy Acetone.

Triose sugar, 1,3-dihydroxy acetone (DHA) on treatment with Fenton's reagent releases CO under physiological conditions. The release of CO has been demonstrated by myoglobin assay and quantum chemical studies. The mechanistic study has been carried out using B3LYP/6-311++G(d,p), M06-2X/6-311++G(d,p) and CCSD(T)//M06-2X/6-311++G(d,p) level of theories in aqueous medium with dielectric constant of 78.39 by employing the polarized continuum model (PCM). The theoretical investigation shows that DHA breaks down completely into 2 equiv of CO, 1 equiv of CO2, and 6 equiv of H2O without formation of toxic metabolites. The activation barriers of some steps are as high as ∼50 kcal mol-1 along with barrierless intermediate steps resulting from highly stabilized intermediates. The quantum tunneling mechanism of proton transfer steps has been confirmed through kinetic isotope effect study. The natural bond orbital analysis is consistent with the proposed mechanism. The present protocol does not require any photoactivation and thus it can serve as a promising alternative to transition metal CO-releasing molecules. The present work can initiate the study of carbohydrates as CO-releasing molecules for therapeutic applications and it could also be useful in generation of CO for laboratory applications.

Computational modelling of nanotube delivery of anti-cancer drug into glutathione reductase enzyme.

Density functional theory method combined with docking and molecular dynamics simulations are used to understand the interaction of carmustine with human glutathione reductase enzyme. The active site of the enzyme is evaluated by docking simulation is used for molecular dynamics simulation to deliver the carmustine molecule by (5,5) single walled carbon nanotube (SWCNT). Our model of carmustine in the active site of GR gives a negative binding energy that is further refined by QM/MM study in gas phase and solvent phase to confirm the stability of the drug molecule inside the active site. Once released from SWCNT, carmustine forms multiple polar and non-polar hydrogen bonding interactions with Tyr180, Phe209, Lys318, Ala319, Leu320, Leu321, Ile350, Thr352 and Val354 in the range of 2-4 Å. The SWCNT vehicle itself is held fix at its place due to multiple pi-pi stacking, pi-amide, pi-sigma interactions with the neighboring residues. These interactions in the range of 3-5 Å are crucial in holding the nanotube outside the drug binding region, hence, making an effective delivery. This study can be extended to envisage the potential applications of computational studies in the modification of known drugs to find newer targets and designing new and improved controlled drug delivery systems.

Size matters! The largest wild stump-tailed macaque Macaca arctoides troop ever reported, located in the Hollongapar Gibbon Sanctuary, northeastern India.

Very large and stable, socially coherent primate groups, not including fission-fusion societies, are usually rare in nature, owing to constraints imposed by various ecological and social factors. Moreover, unlike species in open habitats, those in forests tend to have smaller groups, and this becomes further accentuated in small and fragmented forest patches. We report here an unusually large troop of stump-tailed macaques Macaca arctoides from the Hollongapar Gibbon Sanctuary, a small and isolated lowland tropical rainforest patch in the Upper Brahmaputra Valley of northeastern India - this is possibly the largest wild group of the species recorded anywhere across its distribution range. We hypothesise the potential factors driving the formation of such a large social group of this vulnerable cercopithecine primate and discuss the conservation implications of this phenomenon.

Unveiling the Role of Hydrogen Bonding and g-Tensor in the Interaction of Ru-Bis-DMSO with Amino Acid Residue and Human Serum Albumin.

Density functional theory calculations have been carried out to observe the role of hydrogen bonding in hydrolysis and the coordination mechanism of three amino acid residues (histidine, cysteine, and alanine) with Ru-bis-DMSO complex via which the complex tends to interact with the HSA protein receptor. The interaction mechanism shows that ruthenium complexes prefer to bind protein receptor through cysteine and histidine residues rather than through alanine, which has been confirmed by DFT evaluated H-bonding and g-tensor analysis. The number of H-bonds plays a major role in stabilizing the intermediates and transition states involved in the Ru-bis-DMSO and amino acid residue interactions. Our theoretical g-tensor values are in good agreement with the available experimental results. Further QM/MM calculation on the Ru-bis-DMSO-HSA adducts reveals that the adduct is more stable when Ru gets coordinated with histidine imidazole rather than cysteine. These investigations helped us in understanding the type of amino acid residue responsible for binding the metal complex Ru-bis-DMSO with the carrier protein HSA.

Quantum Chemical Studies on Detail Mechanism of Nitrosylation of NAMI-A-HSA Adduct.

Hydrolysis of NAMI-A in NAMI-A-HSA (HSA = human serum albumin) and nitrosylation of hydrolyzed NAMI-A-HSA adduct have been studied in detail using density functional theory method. It has been observed that the chloride exchange reaction with water in the NAMI-A-HSA adduct follows an interchange dissociative mechanism passing through an unstable heptacoordinated activated complex. The computed free energy of activation (ΔG) and rate constant (k) for the hydrolysis process in aqueous medium are observed to be 24.85 kcal mol(-1) and 3.81 × 10(-6) s(-1), respectively. Nitrosylation of hydrolyzed NAMI-A-HSA adduct with nitric oxide is found to be thermodynamically more favorable with the incorporation of solvent effect and provides a detailed understanding related to the antimetastatic activity of the NAMI-A drug. This investigation shows that nitric oxide coordinates linearly to NAMI-A-HSA adduct leading to the reduction of ruthenium(III) to more active ruthenium(II), with the reduction potential of -2.32 V. Negative relative solvation and relative binding free energies suggest that the hydrolysis and nitrosylation reactions are found to be thermodynamically favorable and faster. Our computed results provide a detailed thermodynamics and kinetics which may be highly beneficial for understanding antimetastatic activity as well as the nitric oxide scavenging ability of NAMI-A.

Novel water soluble neutral vanadium(IV)-antibiotic complex: Antioxidant, immunomodulatory and molecular docking studies.

A novel water soluble five coordinate oxovanadium(IV) complex, [VO(C16H15N4O8S)HSO4] incorporating cefuroxime, a cephalosporin group of antibiotic have been prepared from an interaction of vanadyl sulfate and cefuroxime in aqueous solution. The compound was characterized by Fourier transform infrared spectroscopy (FTIR), CHN microanalyses, ultraviolet-visible spectroscopy (UV-Vis), fast atom bombardment (FAB) mass spectrometry and thermogravimetric analysis (TGA). Density Functional Theory (DFT) computation using Gaussian 09 program at B3LYP level revealed a distorted square pyramidal energy optimized geometry for the vanadyl(IV) complex. The molecular docking studies show that the interaction between the vanadium complex and protein receptor, clathrin is dominated by hydrophobic forces. The experimental (1)H nuclear magnetic resonance (NMR) features of the analogous Zn(II) complex matched well with the theoretically computed values further affirming the distorted square pyramidal geometry for the vanadyl(IV) complex. Cyclic voltammetry revealed a metal centered single-electron oxidation-reduction response for VO(IV)/VO(V) couple. The antioxidant activity of the vanadium(IV)-complex vis-à-vis the antibiotic has been assessed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. The vanadium complex showed comparatively better radical scavenging ability compared to the antibiotic cefuroxime. The antimicrobial activity of the compound has been assayed for five different microbial strains using minimum inhibitory concentration (MIC) method. Immunomodulatory studies carried out using phagocytosis index, myeloperoxidase release and cytokine assay indicated the vanadium(IV)-complex to be immunosuppressant. The cytotoxicity of the compound was evaluated by MTT (3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) reduction assay.