Inhibitory potential of furanocoumarins against cyclin dependent kinase 4 using integrated docking, molecular dynamics and ONIOM methods.

Cyclin Dependent Kinase 4 (CDK4) is vital in the process of cell-cycle and serves as a G1 phase checkpoint in cell division. Selective antagonists of CDK4 which are in use as clinical chemotherapeutics cause various side-effects in patients. Furanocoumarins induce anti-cancerous effects in a range of human tumours. Therefore, targeting these compounds against CDK4 is anticipated to enhance therapeutic effectiveness. This work intended to explore the CDK4 inhibitory potential of 50 furanocoumarin molecules, using a comprehensive approach that integrates the processes of docking, drug-likeness, pharmacokinetic analysis, molecular dynamics simulations and ONIOM (Our own N-layered Integrated molecular Orbital and Molecular mechanics) methods. The top five best docked compounds obtained from docking studies were screened for subsequent analysis. The molecules displayed good pharmacokinetic properties and no toxicity. Epoxybergamottin, dihydroxybergamottin and notopterol were found to inhabit the ATP-binding zone of CDK4 with substantial stability and negative binding free energy forming hydrogen bonds with key catalytic residues of the protein. Notopterol exhibiting the highest binding energy was subjected to ONIOM calculations wherein the hydrogen bonding interactions were retained with significant negative interaction energy. Hence, through these series of computerised methods, notopterol was screened as a potent CDK4 inhibitor and can act as a starting point in successive processes of drug design.Communicated by Ramaswamy H. Sarma.

Design of LNA Analogues Using a Combined Density Functional Theory and Molecular Dynamics Approach for RNA Therapeutics.

Antisense therapeutics treat a wide spectrum of diseases, many of which cannot be addressed with the current drug technologies. In the quest to design better antisense oligonucleotide drugs, we propose five novel LNA analogues (A1-A5) for modifying antisense oligonucleotides and establishing each with the five standard nucleic acids: adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U). Monomer nucleotides of these modifications were considered for a detailed Density Functional Theory (DFT)-based quantum chemical analysis to determine their molecular-level structural and electronic properties. A detailed MD simulation study was done on a 14-mer ASO (5'-CTTAGCACTGGCCT-3') containing these modifications targeting PTEN mRNA. Results from both molecular- and oligomer-level analysis clearly depicted LNA-level stability of the modifications, the ASO/RNA duplexes maintaining stable Watson-Crick base pairing preferring RNA-mimicking A-form duplexes. Notably, monomer MO isosurfaces for both purines and pyrimidines were majorly distributed on the nucleobase region in modifications A1 and A2 and in the bridging unit in modifications A3, A4, and A5, suggesting that A3/RNA, A4/RNA, and A5/RNA duplexes interact more with the RNase H and solvent environment. Accordingly, solvation of A3/RNA, A4/RNA, and A5/RNA duplexes was higher compared to that of LNA/RNA, A1/RNA, and A2/RNA duplexes. This study has resulted in a successful archetype for creating advantageous nucleic acid modifications tailored for particular needs, fulfilling a useful purpose of designing novel antisense modifications, which may overcome the drawbacks and improve the pharmacokinetics of existing LNA antisense modifications.

Tuning the transition barrier of H2 dissociation in the hydrogenation of CO2 to formic acid on Ti-doped Sn2O4 clusters.

A density functional theory study has been performed to investigate cation-doped Sn2O4 clusters for selective catalytic reduction of CO2. We study the influence of Si and Ti dopants on the height of the H2 dissociation barrier for the doped systems, and then the subsequent mechanism for the conversion of CO2 into formic acid (FA) via a hydride pinning pathway. The lowest barrier height for H2 dissociation is observed across the 'Ti-O' bond of the Ti-doped Sn2O4 cluster, with a negatively charged hydride (Ti-H) formed during the heterolytic H2 dissociation, bringing selectivity towards the desired FA product. The formation of a formate intermediate is identified as the rate-determining step (RDS) for the whole pathway, but the barrier height is substantially reduced for the Ti-doped system when compared to the same steps on the undoped Sn2O4 cluster. The free energy of formate formation in the RDS is calculated to be negative, which reveals that the hydride transfer would occur spontaneously. Overall, our results show that the small-sized Ti-doped Sn2O4 clusters exhibit better catalytic activity than undoped clusters in the important process of reducing CO2 to FA when proceeding via the hydride pinning pathway.

Recent Advances in Nanoarchitectonics of SnO2 Clusters and Their Applications in Catalysis.

Tin dioxide nanoclusters are very effective as catalysts for various reactions including CO2 conversion and Friedel-Crafts acylation for pharmaceuticals. The nanoarchitectonics of SnO2 could be controlled by different synthetic strategies. In the current article, we have presented synthesis of SnO2 nanoclusters and their applications in catalysis. We have also reviewed computational studies on SnO2 nanoclusters for using them in nanoarchitectonics and catalytic conversion of CO2 to useful chemicals. Optimized structures of various cluster sizes are presented. The present and future perspectives of SnO2 catalysts in biomass conversions are also given.

Oxidation pathways, kinetics and branching ratios of chloromethyl ethyl ether (CMEE) initiated by OH radicals and the fate of its product radical: an insight from a computational study.

The OH-initiated oxidation reactions of chloromethyl ethyl ether (CH2ClOCH2CH3) have been presented by using quantum calculation methods. The Minnesota functional (M06-2X) of the density functional theory method along with a polarization and diffuse 6-311++G(d,p) basis set is chosen for optimization and frequency calculations for H-abstractions from CH2ClOCH2CH3 molecules by OH radicals. Furthermore, the CCSD(T) method along with the same basis set is used for energy refinement of all optimized structures to obtain more accurate energies of the species. Our thermo-chemical calculation results show that the C˙HClOCH2CH3 product radical is more stable, corresponding to hydrogen atom abstraction from the -CH2Cl site, than others while the energy profile results indicate that the H-atom abstracted from the -OCH2 site follows the minimum energy path compared to other channels. The rate constants are computed using canonical transition state theory (CTST) within the temperature range of 250-450 K at 1 atm. The overall rate constant (at 298 K) for the abstraction reactions is found to be consistent with the earlier reported rate constant. The percentage branching ratios of different abstraction channels and the lifetime of chloromethyl ethyl ether are also given herein. We further investigated the unimolecular decomposition pathways of the CH2ClOCH(O˙)CH3 radical and found that unimolecular C-C bond scission is the kinetically and thermodynamically more feasible pathway compared to other unimolecular decomposition reactions.

Structural insight into antisense gapmer-RNA oligomer duplexes through molecular dynamics simulations.

There is an extensive research carrying out on antisense technology and the molecules entering into clinical trials are increasing rapidly. Phosphorothioate (PS) is a chemical modification in which nonbridged oxygen is replaced with a sulfur, consequently providing resistance against nuclease activity. The 2'-4' conformationally restricted nucleoside has the structural features of both 2'-O-methoxy ethyl RNA (MOE), which shows good toxicity profile, and locked nucleic acid (LNA), which shows good binding affinity towards the target RNA. These modifications have been studied and suggested that they can be a potential therapeutic agents in antisense therapy. Mipomersen (ISIS 301012), which contains the novel nucleoside modification has been used to target to apolipoprotein (Apo B), which reduces LDL cholesterol by 6-41%. In this study, classical molecular dynamics (MD) simulations were performed on six different antisense gapmer/target-RNA oligomer duplexes (LNA-PS-LNA/RNA, RcMOE-PS-RcMOE/RNA, ScMOE-PS-ScMOE/RNA, MOE-PS-MOE/RNA, PS-DNA/RNA and DNA/RNA) to investigate the structural dynamics, stability and solvation properties. The LNA, MOE nucleotides present in respective duplexes are showing the structure of A-form and the PS-DNA nucleotides resemble the structure of B-form helix with respect to some of the helical parameters. Free energy calculations suggest that the oligomer, which contains LNA binds to the RNA strongly than other modifications as shown in experimental results. The MOE modified nucleotide, which although had a lower binding affinity but higher solvent accessible surface area (SASA) compared to the other modifications, may be influencing the toxicity and hence may be used it in Mipomersen, the second antisense molecule which is approved by FDA. Communicated by Ramaswamy H. Sarma.

Understanding the Atmospheric Oxidation of HFE-7500 (C3F7CF(OC2H5)CF(CF3)2) Initiated by Cl Atom and NO3 Radical from Theory.

Kinetics and mechanistic pathways for atmospheric oxidation of HFE-7500 ( n-C3F7CF(OCH2CH3)CF(CF3)2) initiated by Cl atom and NO3 radical have been studied using density functional theory. Oxidative degradation pathways facilitated by H-abstraction from the -OCH2 or -CH3 groups in HFE-7500 have been considered. It has been shown that H-abstraction from the α-site (-OCH2) is favored over other reaction pathways. The rate constants were computed employing transition-state theory and canonical variation transition-state theory incorporating small curvature tunnelling correction, over the temperature range of 250-450 K at atmospheric pressure. Calculated rate constants at 298 K and 1 atm compare well with earlier experiments. Temperature dependence of the rate constants and branching ratios for these pathways contributing to overall reaction are described. It has been shown that the rate constants over the studied temperature range was found to fit well to the modified Arrhenius equation (in cm3 molecule-1 s-1) kCl = 1.10 × 10-14  T0.04 exp(-69.87 ± 1.41/T) and kNO3 = 7.66 × 10-26 T3.30 exp(596.40 ± 1.22/T). Standard enthalpies of formation for the reactant (C3F7CF(OCH2CH3)CF(CF3)2) and the products [C3F7CF(OC•HCH3)CF(CF3)2 and C3F7CF(OCH2C•H2)CF(CF3)2] during H-abstraction are derived using the isodesmic approach. Atmospheric implications of the titled molecule are presented.

Modulation of the coordination environment: a convenient approach to tailor magnetic anisotropy in seven coordinate Co(II) complexes.

The possibility of controlling magnetic anisotropy by tuning contribution of second order perturbation to spin-orbit coupling through modulation of the coordination environment is investigated. Subtle variation of the coordination environment triggers a remarkable deviation in the axial zero field splitting parameter of seven coordinate Co(II) complexes.

A new on-fluorescent probe for manganese (II) ion.

A new fluorescent probe for Mn(2+) ion, (6E)-N-((E)-1,2-diphenyl-2-(pyridin-2-ylimino)ethylidene)pyridin-2-amine (L), has been synthesized from benzil and 2-amino pyridine and characterized. In 1:1 (v/v) CH3CN:H2O (pH 4.0, universal buffer) L exhibits fluorescent intensity with emission peak at λmax 360 nm on excitation with photons of 310 nm. Fluorescent intensity of L increases distinguishingly on interaction with Mn(2+) ion compared to metal ions--Na(+), K(+), Ca(2+), Mg(2+), Ba(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), Pb(2+) and Ag(+) individually or all together. The enhancement in fluorescent intensity is due to snapping of photoinduced electron transfer (PET) prevailed in free L. Fluorescence and UV/visible spectral data analysis shows that binding stoichiometry between Mn(2+) and L is 1:1 with log ß ≈ 3.0. Both L and its Mn(2+) complex were optimised using density functional theory (DFT) and vibrational frequency calculations confirm that both are at local minima on the potential energy surfaces.

The first bifluoride sensor based on fluorescent enhancement.

The first fluorescent sensor for HF2(-) anion, N(1), N(3)-di(naphthalene-1-yl)isophthalamide (L) has been derived from α-Napthylamine and isopthaloyl chloride. In 1:1 (v/v) DMSO:H2O, L exhibits high selectivity towards HF2(-) anion with a 4-fold enhancement in fluorescent intensity. Very little enhancement in fluorescence intensity is observed for F(-), Cl(-), Br(-), I(-), SCN(-), PO4(3-), SO4(2-), and CH3COO(-) anions. The stoichiometry interaction between L and HF2 (-) is found to be 1:1 from fluorescence and UV/Visible spectral data. DFT calculation shows that binding between HF2(-) and L is 1:1 and increases the relative planarity between the two naphthyl rings causing fluorescence enhancement. A shift of 0.080 V in oxidation potential of L is observed on interaction with HF2(-) by cyclic voltammetry and square wave voltammetry.

Comparison of all sites for Ti substitution in zeolite TS-1 by an accurate embedded-cluster method.

We studied the preferential location of Ti centers in the framework of the Ti-containing MFI zeolite TS-1 using a hybrid DFT/MM embedding method developed recently. This "covalent elastic polarizable environment" (covEPE) cluster embedding allows a complete and self-consistent treatment of solid covalent systems such as zeolites. For the present study, we used a gradient-corrected density functional approach. The resulting structural features of both Si- and Ti-substituted forms of the zeolite framework fit well with available experimental information. The calculated substitution energy of Ti at the 12 crystallographically different tetrahedral sites of the MFI structure vary within 19 kJ/mol with T12 and T2 as most and least preferred sites, respectively. On the basis of these computational results and the preferential sites for Ti substitution reported from different experimental investigations, we concluded that the Ti distribution in the TS-1 framework is not governed by the thermodynamic stability of the pure material.

Developing the molecular modelling of diffusion in zeolites as a high throughput catalyst screening technique.

Molecular modelling techniques have been used to screen zeolite catalysts for their suitability for organic synthesis. For example, we have used these techniques to study the alkylation of aromatic molecules which are important in the fine-chemical and drug industries. A survey of all such efforts is reviewed in this article. The application of molecular modelling techniques in a systematic manner is an efficient first step in the design of zeolite catalysts. As a qualitative screening tool, molecular graphics is used to visualize how well the reactant and product molecules fit inside the pores of the zeolites. Using a hybrid of several molecular modelling methods, which combines molecular dynamics (MD) and Monte Carlo methods with energy minimization, it is possible to determine the minimum energy locations of the molecules inside the zeolites cages. The minimum energy configurations determined by this hybrid method are taken as a starting point for diffusion of the molecules through the zeolite channels. When a molecule is allowed to diffuse through zeolite channel, the molecule attains some maxima and minima in its diffusion energy profile. From the differences between a maximum and a minimum energy configuration, the diffusion energy barrier for the molecule can be calculated in the zeolites. By comparing the diffusion energy barriers for various isomers of a molecule in different zeolites, it is possible to find out the most suitable zeolite for achieving the required shape-selectivity. In addition, factors influencing the diffusivity of the molecules and consequently the shape selectivity are derived. The list of factors and their relative importance are analysed to derive valuable guidelines to design shape-selective zeolite catalysts for a given reaction. Thus, the ultimate aim of these studies is to develop a high throughput computational screening process for the selection of shape-selective zeolite catalysts for various reactions. The dynamic behaviour of molecules inside the pores of zeolites can be studied using MD methods. Since MD is computationally time consuming, it is more efficient to screen the possible zeolite catalysts by energy minimization methods and then perform MD in specific zeolites. More accurate values of diffusivity of the molecules can be calculated using MD methods, and these values can be correlated with the shape-selectivity observed experimentally and /or derived from diffusion energy barrier calculations.