In Silico Screening Of Zinc Database For Discovery Of Novel Urease Inhibitors As A Remedy To Gastro-Duodenal Ulcer Caused By Helicobacter Pylori

Design and synthesis of novel urease inhibitors taking center stage now days with specific attention as a remedy to Helicobacter pylori infection. A number of inhibitors fail in vivo and in clinical trial owing to the toxicity and hydrolytic profile. In the present study, we are making an attempt to screen a large small molecule database, ZINC, for a potential urease inhibitor. The structure based drug discovery approach has been adopted with acceptable ADMET parameters so that the lead molecules may have fair chances of passing in vitro and in vivo trails. The lead molecule in our study, with ID ZINC90446454 is a urea derivative and predicted to be nontoxic. It comes out to be a promising drug candidate with pKd value 7.83, LE 0.429 and LD50 value 10100 mg/kg body weight. Its sulfanyl derivative, with predicted high LD50 (10100 mg/kg body weight), exhibits the feasibility of a disulfide covalent bond with Cys321 in the active site. The derivative may serve as a novel covalent inhibitor with high specificity, high potency and low toxicity. The derivative, in future, may be a successful drug candidate for H. pylori induced gastro-duodenal ulcer.

To Study The Significance Of Processing Variables Using Quality By Design For Optimization Of Nanoparticulate System Of Cilnidipine

This investigation aimed to prepare Cilnidipine Nanoparticles by nanoprecipitation ultrasonication method and to study the significance of processing variables by applying quality by design. Cilnidipine is fourth-generation dual L/N-type Ca2+ channel blocker used for the management of hypertension. It is BCS class-II drug exhibiting lower aqueous solubility, which tends to lower bioavailability. The combination of Poloxamer 188 and Tween 80 was used as a stabilizer. The design of the experiment is one of the tools of Quality by design. Plackett -Burman design was applied for the screening of processing variables, which are significant for the method. The processing variables screened were stirring speed, antisolvent ratio, drug concentration, polymer concentration, stabilizer concentration. The effect of each parameter evaluated by particle size, entrapment efficiency, and drug release at 10 minutes of prepared Nanoparticles of Cilnidipine. Analysis of variance and Pareto-plot of Plackett-Burman design were utilized to find the significance of the factor and extent of the effect. The surface morphology of Cilnidipine Nanoparticles was studied by SEM. The Pareto plot, as well as statistical analysis of design, had shown that the Concentration of drug, solvent: antisolvent ratio and concentration of poloxamer 188 were the significant parameters for the method. The stabilizer concentration, the stirring speed, and the antisolvent ratio had a negative effect of while the concentration of drug has a positive effect on the particle size of Nanoparticles and drug release at 10 minutes and positive effect of entrapment efficiency of Cilnidipine Nanoparticles. The Cilnidipine Nanoparticles were characterized by FTIR and DSC analysis.

A model for the organization of chlorophyll-protein complex of photosystem II and analysis of its photochemical efficiency and excitation migration.

A model is proposed for the organization of chlorophyll-protein complex in photosystem II (PS II) of higher plants. The rates of exciton migration and exciton trapping have been computed using stochastic method to find out the photochemical efficiency of the dimeric PS II. Three dimeric PS II units are assumed to form a group, as transfer of the exciton to the light harvesting bed of the nearest neighbour on either side may only be effective. A relationship has been deduced between the fractions of the reaction centre traps closed and the number of jumps (J) required by the exciton for trapping. The photochemical efficiency and fluorescence quantum yield are computed using J as the parameter in an empirical equation.

Modelling a binuclear metal binding site in the photosynthetic reaction centre II.

Based on the experimental data and homologous sites in Protein Data Bank (PDB) a model for metal binding sites in D1/D2 heterodimer has been proposed. On searching for tetranuclear and binuclear Mn binding sites in the PDB, a suitable sequence homology in thermolysin and D1 could be observed. From the homology and site-directed mutagenesis data, a model for binuclear Mn-Ca or Mn-Mn has been built and it is extended to a tetranuclear Mn centre.

Prediction of structure of antenna proteins of photosystem II.

Membrane spanning regions of 43 kDa and 47 kDa antenna proteins of photosystem II of thylakoid membranes are theoretically predicted. Prediction of topology of chlorophyll-a and beta-carotene molecules in the proteins and interaction of the proteins with 33 kDa extrinsic protein on the lumenal side of thylakoid membrane is based on the findings reported earlier. Each antenna protein is predicted to have six transmembrane alpha-helices with twelve chlorophyll-a and five beta-carotene molecules binding to it. Both N- and C- terminal ends are proposed to be on the stromal side of thylakoid membrane. The proposed structural model conforms to the reported experimental results from the literature.

Prediction of structure and organisation of chlorophyll a/b binding polypeptides in PS I and II.

Secondary structures, functionally important residues, antigenic sites, membrane spanning segments and hydropathicity of light harvesting chlorophyll a/b binding polypeptides (LHC) are predicted by theoretical methods from the amino acid sequence of the polypeptides. The reported structural features of the Pea LHC (Lhcb 1 gene product) from electron crystallographic studies have been compared by alignment with other types of chlorophyll a/b binding polypeptides for structural prediction. Fifteen conserved residues D85, D89, E113, H116, E/Q133, E/Q181, E189, D/N233, E252, N/H255, Q/E269, E/D/Q280, N281, H285, D288 (number indicates position in the aligned sequence), are identified which are potential ligands to Mg2+ of chlorophylls. Three amino acid residues D89, E/Q131 and D/N 233 are proposed as ligands to chlorophylls b2, a7 and b2 respectively, for which ligands are not identified in electron crystallographic study.

Prediction of the conformation of D1/D2 heterodimer of photosynthetic reaction centre II using a modified Chou-Fasman method.

Chou-Fasman method was modified to account for amphipathic nature of Gly and hydrophobic environment. The modified method shows improvement in prediction accuracy from 35 to 70% and can be applied to predict the conformation of D1, D2 polypeptides of reaction centre II of thylakoid, which are analogous to L and M respectively. Possible sites for Mn binding to D1/D2 heterodimer are postulated.

Evolution of oxygen evolving reaction center-II of thylakoids.

A model for evolution of oxygen evolving reaction center II of higher plant initiating from a chlorophyll--quinone complex is proposed. The reaction center gradually incorporates pheophytin, Fe and Mn to finally achieve oxidation of water to oxygen. The structural and functional pattern during evolution is proposed to descend from higher order of symmetry to lower one.