Discovery of novel inhibitors for <Emphasis Type="Italic">Leishmania</Emphasis> nucleoside diphosphatase kinase (NDK) based on its structural and functional characterization

Nucleoside diphosphate kinases (NDKs) are ubiquitous enzymes that catalyze the transfer of the γ-phosphate moiety from an NTP donor to an NDP acceptor, crucial for maintaining the cellular level of nucleoside triphosphates (NTPs). The inability of trypanosomatids to synthesize purines de novo and their dependence on the salvage pathway makes NDK an attractive target to develop drugs for the diseases they cause. Here we report the discovery of novel inhibitors for Leishmania NDK based on the structural and functional characterization of purified recombinant NDK from Leishmania amazonensis. Recombinant LaNDK possesses auto-phosphorylation, phosphotransferase and kinase activities with Histidine 117 playing an essential role. LaNDK crystals were grown by hanging drop vapour diffusion method in a solution containing 18% PEG-MME 500, 100 mM Bis-Tris propane pH 6.0 and 50 mM MgCl₂. It belongs to the hexagonal space group P6₃22 with unit cell parameters a?=?b?=?115.18, c?=?62.18 Å and α?=?β?=?90°, γ?=?120°. The structure solved by molecular replacement methods was refined to crystallographic R-factor and R_free values of 22.54 and 26.52%, respectively. Molecular docking and dynamics simulation-based virtual screening identified putative binding compounds. Protein inhibition studies of selected hits identified five inhibitors effective at micromolar concentrations. One of the compounds showed ~45% inhibition of Leishmania promastigotes proliferation. Analysis of inhibitor-NDK complexes reveals the mode of their binding, facilitating design of new compounds for optimization of activities as drugs against leishmaniasis.     

Physicochemical studies on bioactive Cr(III) coordination compounds with esters of hydrazine carboxylic acid as hetero donor ligands

Reaction between hydrazine derivative ligands (HrzE) or (HrzB) and chromium salt in 1:2 (metal:ligand) molar ratio yielded monometallic trivalent coordination compounds with general formula [Cr(HrzE)₂X₂]X and [Cr(HrzB)₂X₂]X, where (HrzE) = hydrazine carboxylic acid ethyl ester, (HrzB) = hydrazine carboxylic acid tert-butyl ester, and X = Cl^?, Br^? or F^?. Elemental analysis, conductivity measurements, magnetic moment measurements, and various spectroscopic techniques, viz. infrared, ultraviolet–visible, and electrospray ionization mass spectrometry, were applied to illustrate the structure and composition of the coordination compounds. Analytic and conductivity results were consistent with 1:1 electrolytic behavior and the proposed formulas of the coordination compounds. Electronic absorption data and magnetic moment parameters indicated octahedral geometry surrounding the metal ion in the coordination compounds. The in vitro antimicrobial behavior of the ligands and coordination compounds was screened using four bacterial strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella typhi) and two fungal strains (Candida parapsilosis and Saccharomyces cerevisiae). The results indicated improved activity of the coordination compounds compared with the free ligands against the studied bacteria and fungi.     

Inhibition effect of pomelo peel extract for N80 steel in 3.5% NaCl saturated with CO2 solution

Research on Chemical Intermediates - Pomelo peel extract (PPE) has been evaluated as a corrosion inhibitor for N80 steel in 3.5% NaCl saturated with CO2 solution using weight loss measurements,...     

Synthesis of threo- and erythro-configured trihydroxy open chain lipophilic ketones as possible anti-mycobacterial agents

A series of threo- and erythro-configured open-chain trihydroxy ketones was synthesized starting from l- and d-ascorbic acid respectively as the starting material, through the use of Grignard reactions for the requisite CC bond formations. The lipophilic ketones were screened against Mycobacteriumtuberculosis for anti-proliferative activity. The lipophilic ketones with tetradecyl alkyl side chains were found to be moderately active against cell proliferation.     

Synthesis and evaluation of a tri-armed molecular receptor for recognition of mercury and cyanide toxicants

A tri-armed-pyrene-linked molecular receptor, 5 has been designed, synthesised and evaluated for ionic recognition. It has been observed that the synthesised molecular receptor can recognise mercury and cyanide ions through a change in colour, UV–Vis and fluorescence intensity. The binding stoichiometry of the receptor and these ionic species has been found to be 1:1 through Job’s plots, Benesi–Hildebrand plots and isothermal titration calorimetry (ITC).     

Molecular dynamics and pharmacophore modelling studies of different subtype (ALK and EGFR (T790M)) inhibitors in NSCLC

Extensively validated 3D pharmacophore models for ALK (anaplastic lymphoma kinase) and EGFR (T790M) (epithelial growth factor receptor with acquired secondary mutation) were developed. The pharmacophore model for ALK (r² = 0.96, q² = 0.692) suggested that two hydrogen bond acceptors and three hydrophobic groups arranged in 3-D space are essential for the binding affinity of ALK inhibitors. Similarly, the pharmacophore model for EGFR (T790M) (r² = 0.92, q² = 0.72) suggested that the presence of a hydrogen bond acceptor, two hydrogen bond donors and a hydrophobic group plays vital role in binding of an inhibitor of EGFR (T790M). These pharmacophore models allowed searches for novel ALK and EGFR (T790M) dual inhibitors from multiconformer 3D databases (Asinex, Chembridge and Maybridge). Finally, the eight best hits were selected for molecular dynamics simulation, to study the stability of their complexes with both proteins and final binding orientations of these molecules. After molecular dynamics simulations, one hit has been predicted to possess good binding affinity for both ALK and EGFR (T790M), which can be further investigated for its experimental in-vitro/in-vivo activities.     

First report of isolation of maleamic acid from natural source Polygonatum cirrhifolium—A potential chemical marker for identification

Polygonatum cirrhifolium (Meda) plant is being used in number of rejuvenating Ayurvedic formulations. Ever rising demands, lack of natural sources, and insufficient quantity, to meet the requirements of market, the raw material has led toward the use of official substitutes recommended by the Department of AYUSH that has further encouraged manufacturers for adulteration of formulations by other substandard/spurious raw drugs. Literature reveals that more than 60% Ayurvedic parameters as well as pharmacological actions of Ashtawarga plants do not match with their substitutes leading to reduced efficacy of the drugs along with loss of faith for use of herbal drugs. Consumers are forced to pay for the material which has never been used for high-cost claimed formulation. The situation is being exploited by manufacturers because regulatory authorities lack the tools (marker compound) needed for identification of authentic plant. Methanolic extract of rhizomes of plant was subjected to column chromatography. Isolated compound has been characterized as (Z)-4-amino-4-oxobut-2-enoic acid (maleamic acid/maleamate/maleic monoamide/maleic acid monoamide) by chemical test, melting point, IR/NMR/mass/UV spectral analysis. It is the first report in Polygonatum genus and can be used as a marker for identification of the plant in market formulations.     

Multi-objective Geometry Optimization of a Gas Cyclone Using Triple-Fidelity Co-Kriging Surrogate Models

Cyclone separators are widely used in a variety of industrial applications. A low-mass loading gas cyclone is characterized by two performance parameters, namely the Euler and Stokes numbers. These parameters are highly sensitive to the geometrical design parameters defining the cyclone. Optimizing the cyclone geometry therefore is a complex problem. Testing a large number of cyclone geometries is impractical due to time constraints. Experimental data and even computational fluid dynamics simulations are time-consuming to perform, with a single simulation or experiment taking several weeks. Simpler analytical models are therefore often used to expedite the design process. However, this comes at the cost of model accuracy. Existing techniques used for cyclone shape optimization in literature do not take multiple fidelities into account. This work combines cheap-to-evaluate well-known mathematical models of cyclones, available data from computational fluid dynamics simulations and experimental data to build a triple-fidelity recursive co-Kriging model. This model can be used as a surrogate with a multi-objective optimization algorithm to identify a Pareto set of a finite number of solutions. The proposed scheme is applied to optimize the cyclone geometry, parametrized by seven design variables.