Chemistry

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Shiv Nadar University

Theory predicts herein enzymatic activity from scratch. We show that molecular dynamics (MD) simulations and quantum-mechanical/molecular mechanics (QM/MM) calculations of the fatty acid hydroxylase P450 BM3 predict the binding mechanism of the fatty acid substrate and its enantio/regioselective hydroxylation by the active species of the enzyme, Compound I. The MD simulations show that the substrate's entrance involves hydrogen-bonding interactions with Pro25, Glu43, and Leu188, which induce a huge conformational rearrangement that closes the substrate channel by pulling together the A helix and the β1 sheet to the F/G loop. In turn, at the bottom of the substrate's channel, residue Phe87 controls the regioselectivity by causing the substrate's chain to curl up and juxtapose its CH2 positions ω-1/ω-2/ω-3 to Compound I while preventing access to the endmost position, ω-CH3. Phe87 also controls the stereoselectivity by the enantioselective steric blocking of the pro-S C-H bond, thus preferring R hydroxylation. Indeed, the MD simulations of the mutant Phe87Ala predict predominant ω hydroxylation. These findings, which go well beyond the X-ray structural data, demonstrate the predictive power of theory and its insight, which can potentially be used as a partner of experiment for eventual engineering of P450 BM3 with site-selective C-H functionalization capabilities. © 2015 American Chemical Society.

(SoNS) School of Natural Sciences

World University root node

Journal of the American Chemical Society

Molecular Dynamics and QM/MM Calculations Predict the Substrate-Induced Gating of Cytochrome P450 BM3 and the Regio- and Stereoselectivity of Fatty Acid Hydroxylation

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Scientific Reports

Erratum: Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors (Scientific Reports (2016) 6 (26603) DOI: 10.1038/srep26603)

The spiro[pyrrolidine-3, 3-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3 -oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions. © The Author(s) 2016.

Life Sciences

Spiro[pyrrolidine-3, 3-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification

Mono-benzoxazine monomers based polybenzoxazines suffer from a lower crosslink density and char yield that especially is further diluted by the presence of longer alkylene chain in cardanol (C). In order to improve the crosslink density, char yield and to understand the role of higher aromatic content vs functionality, a series of cardanol-based benzoxazine monomers were synthesised. The amine condensed with cardanol and paraformaldehyde were aniline (a), 4-triphenylmethylaniline (ta), and tetra-aminophenyl methane (tapm) via solventless methodology. The C-a and C-ta are mono-benzoxazines while C-tapm is a tetra-benzoxazine monomer. The monomers were structurally characterised using FT-IR, 1H and 13C NMR spectroscopy and mass spectrometry. The ring opening polymerisation temperature (ROP) of monomers and thermal stability of resins was determined using DSC and TGA while mechanical properties were determined using rheometry. The curing kinetic study using FT-IR and DSC showed C-ta has intermediate curing behaviour between the C-a and C-tapm. The Ea for curing reaction C-a, C-ta and C-tapm was found to be 143, 126 and 70 kJ/mol. The lowest Ea for curing reaction of C-tapm (tetra-benzoxazine) is due to its highest functionality but C-ta (mono-benzoxazine) has lower Ea than C-a which can be accounted to the presence of more reactive sites provided by the additional aromatic rings in the former. It was found that the incorporation of higher aromatic ring in benzoxazine monomers is another route in enhancing the crosslink density besides higher functionality to modulate their properties. © 2016 Elsevier Ltd

Polymer

Role of higher aromatic content in modulating properties of cardanol based benzoxazines

Two-dimensional infrared spectroscopy of backbone vibrations maps interactions of natural salmon DNA with its water shell. Fast fluctuations in the 300 fs regime are discerned from quasi-static disorder, establishing the short-range character of electrical interactions.

Optics InfoBase Conference Papers

Hydration of native DNA: Ultrafast structural dynamics and short-range electric fields

We have performed steady state UV-visible absorption and time-resolved fluorescence measurements and computer simulations to explore the cosolvent mole fraction induced changes in structural and dynamical properties of water/dioxane (Diox) and water/tetrahydrofuran (THF) binary mixtures. Diox is a quadrupolar solvent whereas THF is a dipolar one although both are cyclic molecules and represent cycloethers. The focus here is on whether these cycloethers can induce stiffening and transition of water H-bond network structure and, if they do, whether such structural modification differentiates the chemical nature (dipolar or quadrupolar) of the cosolvent molecules. Composition dependent measured fluorescence lifetimes and rotation times of a dissolved dipolar solute (Coumarin 153, C153) suggest cycloether mole-fraction (XTHF/Diox) induced structural transition for both of these aqueous binary mixtures in the 0.1 ≤ XTHF/Diox ≤ 0.2 regime with no specific dependence on the chemical nature. Interestingly, absorption measurements reveal stiffening of water H-bond structure in the presence of both the cycloethers at a nearly equal mole-fraction, XTHF/Diox ∼ 0.05. Measurements near the critical solution temperature or concentration indicate no role for the solution criticality on the anomalous structural changes. Evidences for cycloether aggregation at very dilute concentrations have been found. Simulated radial distribution functions reflect abrupt changes in respective peak heights at those mixture compositions around which fluorescence measurements revealed structural transition. Simulated water coordination numbers (for a dissolved C153) and number of H-bonds also exhibit minima around these cosolvent concentrations. In addition, several dynamic heterogeneity parameters have been simulated for both the mixtures to explore the effects of structural transition and chemical nature of cosolvent on heterogeneous dynamics of these systems. Simulated four-point dynamic susceptibility suggests formation of clusters inducing local heterogeneity in the solution structure. © 2016 AIP Publishing LLC.

Journal of Chemical Physics

Structural anomaly and dynamic heterogeneity in cycloether/water binary mixtures: Signatures from composition dependent dynamic fluorescence measurements and computer simulations

DNA oligomers are studied at 0% and 92% relative humidity, corresponding to N&lt;2 and N&gt;20 water molecules per base pair. Two-dimensional (2D) infrared spectroscopy of DNA backbone modes between 920 and 1120 cm,-1 maps fluctuating interactions at the DNA surface. At both hydration levels, a frequency fluctuation correlation function with a 300 fs decay and a slow decay beyond 10 ps is derived from the 2D lineshapes. The fast component reflects motions of DNA helix, counterions, and water shell. Its higher amplitude at high hydration level reveals a significant contribution of water to the fluctuating forces. The slow component reflects disorder-induced inhomogeneous broadening. © 2015 Author(s).

Structural Dynamics

Ultrafast vibrational dynamics of the DNA backbone at different hydration levels mapped by two-dimensional infrared spectroscopy

Topological properties of chemical library networks, such as the average clustering coefficient, average path length, and existence of hubs, can serve as indicators to describe the inherent complexities of chemical libraries. We have used Diversity-Oriented Synthesis (DOS) and Focussed Libraries to investigate the appearance of scale-free properties and absence of small-world behavior in chemical libraries. DOS aims to elicit structural complexity in small compounds with respect to skeleton, functional groups, appendages and stereochemistry. Complexity here indicates incorporation of sp 3 carbons, hydrogen bond acceptors and donors in the molecule. Biological studies have shown how structural complexity enhances the interaction of molecules with complex biological macromolecules. In contrast, Focussed Libraries concentrate on specific scaffolds against a specific biological target. We have quantified the diversity in several DOS and Focussed Libraries based on properties of similarity and dissimilarity threshold networks formed from them. Similarity and dissimilarity networks were generated from diverse chemical libraries at various Tanimoto similarity coefficients (t c) using FP2 and MACCS fingerprints. The dissimilarity networks at very low t c threshold led to the absence of small-world behaviors, as evidenced by low average clustering coefficient and high average path length in comparison to Erdös–Renyi networks. Dissimilarity networks exhibit scale free topology as evidenced by a power law degree distribution. The similarity networks at high t c threshold have shown high clustering coefficients and low average path lengths, without the appearance of hubs. Combining dissimilarity and similarity threshold graphs revealed assortative and dissortative behaviors in the DOS libraries, leading to the conclusion that the vertices of the dissimilarity communities are more likely to share similarity edges, but it is quite unlikely for the vertices in a similarity community to share dissimilarity edges. We propose a simple and convenient diversity quantification tool, QuaLDI (Quantitative Library Diversity Index) to quantify the diversity in DOS and Focussed libraries. We anticipate that these topological properties can be used as descriptors to quantify the diversity in chemical libraries before proceeding for synthesis. © 2016, Springer International Publishing Switzerland.

Mathematics

Journal of Mathematical Chemistry

Investigation of similarity and diversity threshold networks generated from diversity-oriented and focused chemical libraries

A sulfur-rich copolymer is synthesized via a sustainable, eco-friendly approach using two major wastes namely, elemental sulfur (industrial waste) and cardanol (agro waste) and its application as cathode active material in Li−S battery. The presence of chemically bound sulfur (90 wt\%) utilising cardanol (10 wt\%) derivative in the copolymer (S90) showed a reduction in the active material dissolution into the electrolyte. In addition, the organic sulfur units get dispersed into the insoluble/insulating Li2S2/Li2S phase and thus found to suppress their irreversible deposition. Li−S battery based on S90/multi-walled carbon nanotubes (MWCNT) (10 wt\%) exhibited a reversible capacity of 1302 mAh g−1 at 2nd cycle, maintaining a high reversible capacity of 928 mAh g−1 after 70 cycles at a relatively constant coulombic efficiency over 99 \% at current rate of 200 mA g−1. At 1000 mA g−1 current rate, the composite cathode delivered a reversible capacity of 697 mAh g−1 at 2nd cycle and retained 75 \% of its initial capacity even after 180 cycles. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemistrySelect

Cardanol benzoxazine-Sulfur Copolymers for Li-S batteries: Symbiosis of Sustainability and Performance

A 'direct' alkynylation of isatins, which uses potassium tert-butoxide to provide the desired 3-hydroxy-3-ethynyl-2-oxindoles in good to high yields, is reported. This protocol proceeds smoothly for both electron-rich and electron-deficient alkynes in comparable reaction rates and does not require any specially design ligand or expensive transition-metal catalysts.