D. V. Kohli

QSAR studies on imidazopyridazine derivatives as PfPK7 inhibitors

Quantitative structure–activity relationship (QSAR) studies were carried out on a series of 35 recently synthesised imidazopyridazine derivatives to investigate the structural requirements of their inhibitory activity against malarial kinase, Plasmodium falciparum protein kinase 7 (PfPK7). Partial least square (PLS) methodology coupled with various feature selection methods, viz. stepwise (SW), genetic algorithm (GA) and simulated annealing, was applied to derive QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The statistically significant best 2D-QSAR model having correlation coefficient r 2 = 0.9190 and cross-validated squared correlation coefficient q 2 = 0.8575 with external predictive ability of pred_r 2 = 0.7212 was developed by SW-PLS with the descriptors like StNE-index, T_N_O_2, T_N_O_7, YcompDipole and SaasCE-index. Molecular field analysis was used to construct the best 3D-QSAR model using GA-PLS method, showing good correlative and predictive capabilities in terms of q 2 = 0.7494 and pred_r 2 = 0.8841. The information rendered by 2D- and 3D-QSAR models may lead to a better understanding of structural requirements of PfPK7 inhibitors and also aid in designing novel potent antimalarial molecules.

Molecular Modeling Studies of Substituted 2,4,5-Trisubstituted Triazolinones Aryl and Nonaryl Derivatives as Angiotensin II AT1 Receptor Antagonists

The development of new therapies to treat hypertension and cardiovascular diseases. A series of 2,4,5-trisubstituted triazolinones aryl and nonaryl derivatives were subjected to Group-based QSAR, -nearest neighbour molecular field analysis, and pharmacophore mapping. Multiple linear regression (MLR) methodology coupled with feature selection method namely simulated annealing, was applied to derive Group based QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The best physicochemical descriptors, namely, R1chiV1, R2T_N_O_3, R2chlorines count, R2T_C_N_4, and R2SssNHE index, contribute significantly to the biological activity. The statistically significant best Group-based QSAR model has and with pred_. The 3D-QSAR studies were performed using the simulated annealing selection -nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient and predicate activity pred_ were obtained. Contour maps using this approach showed that steric, electrostatic, and hydrophobic effects dominantly determine binding affinities. Pharmacophore hypotheses were generated by the mol sign module and found to contain common features like hydrogen bond donor acceptor, donor, positive, negative ionizable, and hydrophobic features. This model can be used for preliminary screening of large number of substituted 3H-1,-2,-4 triazolinone aryl and nonaryl derivatives. The information rendered by 3D-QSAR models may lead to a better understanding of structural requirements of triazolinone aryl and nonaryl derivatives and also aid in designing novel potent antihypertensive molecules.

Edible transgenic plant vaccines for different diseases.

Edible plant vaccines are immunogenic preparations containing antigenic proteins rather than pathogens, therefore, they sanctify situation where there is a possibility of resurgence of disease when the antigenic preparation contains the organism in any form whatsoever. Expression of antigens as vaccines and of antibodies against antigens of pathogens in transgenic plants is a convenient and inexpensive source for various bacterial, viral, helminths, protozoan and autoimmune diseases with lower capital costs. This review describes various diseases along with the production of edible transgenic plant vaccines/proteins for the same. Thus, substituting and improvising conventional immunization methods.

Structural Insight for Imidazopyridazines as Malarial Kinase PfPK7 Inhibitors Using QSAR Techniques

With a view to the rational design of a selected series of 35 imidazopyridazine derivatives, 2D and 3D QSAR models have been developed for the prediction of antimalarial activity. The statistically best 2D QSAR model having r(2) = 0.9242 and q(2) = 0.8691 with pred_r(2) = 0.9206 was developed by SW-MLR and best 3D QSAR model having q(2) = 0.8607 with pred_r(2) = 0.8332 was developed by k-nearest neighbor molecular field analysis (kNN-MFA). Molecular docking study was also carried out to better understand of the interactions between PfPK7 enzyme target (pdb: 2pnm) and inhibitors in this series. The docking study suggests that these PfPK7 inhibitors interact with Met120, Lys55, Tyr117, Asp123, Leu179, Leu34, Asn35, Ala53, Glu88, Leu101, Tyr119, Ser124, Ser189 and Asp190 amino acid residues of protein PfPK7. Both QSAR and docking studies of such derivatives provide guidance for further lead optimization and designing of more potent PfPK7 inhibitors.

Probing the structural requirements for angiotensin II receptor: molecular modeling studies

The present study describes the development of 3D-QSAR studies on angiotensin II receptor based on the selected pharmacophore model. A four-point pharmacophore with one hydrogen bond acceptor (A), one hydrophobic (H), and two aromatic ring features (R) as pharmacophore features was developed by PHASE module. The pharmacophore hypothesis yielded a statistically significant model with good partial least-squares results. Thus, obtained 3D-QSAR model with partial least-squares (PLS) factor regression coefficient value (r2 = 0.9547) for training set and high value of cross-validated correlation coefficient Q2 = 0.7418, root-mean-squared error RMSE = 0.1257. This model was found to yield reliable clues for the further optimization of benzimidazole derivatives in the dataset, which plays an important role in molecular drug design approach.

Pharmacophore modeling and 3D-QSAR of novel chalcone derivatives as Plasmodium falciparum growth inhibitors

A fermentation industries utilize complex raw materials to increase profitability. Complex substrates mostly include byproducts of agriculture and allied industries. Although far more economical, complex media pose the problem of batch to batch variability and non-reproducibility. A typical complex media consists of diverse array of substitutable carbon and nitrogen sources, making the characterization of industrial antibiotic process extremely challenging. Carbon and nitrogen source play a central role in the metabolism of the microorganism and thus affect the product yield. Most studies on antibiotic production have been done on defined media. It is thus desirable to characterize the influence of multi-substitutable substrates on growth and product formation in terms of mathematical model. To this end, earlier studies within our research group (Bapat, Bhartiya et al. 2006) have established structured kinetic models for Amycolatopsis mediterranei S699 (a rifamycin B producer) in complex medium. One of the important building blocks of these models is the hypothetical enzyme(s) responsible for the uptake of certain substrate. But in earlier studies no attempt has been made to measure these enzymes experimentally, but have been expressed as a latent parameter. We have attempted here to quantify these latent parameters experimentally. To this end we have used two approaches, viz., (1) oxygen uptake based oxygraph studies (where the rate of oxygen uptake is used as an indirect measure of substrate uptake rate) and (2) confirmatory approach based on uptake of 14C-labeled substrate. With this knowledge new substrate feeding strategies could be developed to perform fed-batch fermentation which could lead to increased rifamycin yield. Experimental validation of structured model representing the utilization pattern of substitutable substrates in Rifamycin B fermentation Avinash Sinha and Pramod P WangikarWe have developed here a novel, highly sensitive and selective nitrate (NO − ) biosensor by covalent immobilization of nitrate reductase (NaR) in self-assembled monolayer (SAM) of cysteine on gold nanoparticles (GNP)-polypyrrole (PPy) modified platinum electrode. Incorporation of GNP in highly microporous PPy matrix was confirmed by morphological scanning electron microscope (SEM) images. The electrochemical behavior of the NaR modified electrode exhibited the characteristic reversible redox peaks at the potential, −0.76 and −0.62 V versus Ag/AgCl. Further, the GNP-PPy nanocomposite enhanced the current response by 2-fold perhaps by enhancing the immobilization of NaR and also direct electron transfer between the deeply buried active site and the electrode surface. The common biological interferences like ascorbic acid, uric acid were not interfering with the NO − measurement at low concentration levels. This biosensor showed a wide linearGenomic selection (GS) was proposed in 2001 (Meuwissen et al., 2001).GS is a form of MAS(marker assisted selection), where the whole genome covered by genetic markers in a dense manner are used for estimating the breeding value of selection candidates for a quantitative trait (Goddard, 2009). By applying genomic selection, the selection cycle for selecting elite lines can be shortened and it results in greater gains /unit time and cost (Heffner et al., 2010). In GS estimations are based on more genotyping and less on phenotyping. In case of GS the main purpose of phenotyping is to estimate and re-estimate the marker effects (Heffner et al., 2009). In GS there are two populations (Heffner et al., 2009): Training population (TP) and Breeding population (BP).Based on markers having high breeding value, prediction would be made about BP and lines having high breeding value will be selected for final evaluation in the field. Based on performance of these lines, line performing best could be released as variety. If not used for releasing variety then breeding lines selected based on breeding value could be used for germplasm improvement.P compounds are a complex group of substrates which have gained a great attention in last years because they have important health properties and antioxidant activity. Amperometric biosensors based on peroxidases from Brassica napus hairy roots (PBHR) used to determine t-resveratrol (t-Res) and the total polyphenolic content in wine and tea samples were studied in our laboratory by the first time. The method employs carbon paste (CP) electrodes filled up with PBHR, ferrocene (Fc), and CP or multi-walled carbon nanotubes embedded in a mineral oil (MWCNT + MO) at a given composition (PBHR-Fc-(CP) MWCNT + MO). Biosensors were covered externally with a dialysis membrane, which was fixed at the electrode body side part with a Teflon laboratory film and an O-ring. Calibration curves obtained from steady-state currents as a function of the concentration of a polyphenolic standard reference compound such as t-Res or caffeic acid (CA) were then used to estimate the total polyphenolic content in real samples. Statistical parameters such as reproducibility, repeatability, detection limits, and stability of biosensors were studied, showing a good performance of these devices. Moreover, this analytical methodology has some advantages over the classic HPLC methods, such as: the electrochemical instrumentation is cheaper, a lesser amount of solvents is required and the analysis time can be notably shortened. The comparison with other biosensors will be discussed. Nowadays, studies related to the application of these biosensors to determine polyphenolic compounds in pharmaceutical formulations are being carried out in our laboratory. Amperometric biosensors for the determination of beneficial compounds for human health Maria Alicia Zon Universidad Nacional de Rio Cuarto, ArgentinaG (GK) is the predominant hexokinase that controls hepatic glucose disposal and acts as a glucose sensor for insulin secretion in pancreatic β-cells. Inactivating and activating mutations in GK gene can influence the affinity for glucose that can leads to altered glucose levels in the blood and are responsible for Type 2 diabetes (MODY2). Molecular Dynamics is a powerful computational simulation technique that can produce numerical estimations of physical properties of a molecule by making use of a variety of molecular mechanics force fields. In this study the impact of a total of 42 MODY2 mutations on the confirmation of GK was studied. The list of MODY2 mutations were retrieved from SWISS PROT data base and the X-ray crystallographic structure of pancreatic Glucokinase with resolution of 1.5 Ao was obtained from PDB data base. The intact structure was optimized with PolakRibiere conjugate gradient algorithm at an RMS gradient of 0.1 and dynamics simulations were carried out in AMBER force field for a period of 0.6 ps and a simulation temperature of 300 K. The same procedure was carried out by introducing the MODY2 mutations in the intact GK structure sequentially and the energy values were compared to the intact structure. All the 42 mutated structures were submitted to PDBSum to analyze the variations in the secondary confirmations that are aroused due to each mutation. The results showed there is variation in the Kinetic and Potential energies of mutated structures with respect to intact GK structure. The PDBSum results clearly showed that the induced mutations affected the intact conformation and these conformational changes were seen in Substrate and ATP binding regions also. The results allowed following the influence of mutations on conformational variations of GK structure, especially in the substrate and ATP binding regions. This can help to elucidate the variations in binding affinity of Glucose to the substrate binding region in the MODY2 condition. Mutation induced conformational fluctuations in glucokinase: A molecular dynamics studyT use of biodegradable materials as implants has revolutionized the way medicine is practiced today. Among many biodegradable polymers PLA and PGA have many practical applications. Accurate Modelling of such polymers plays an important role in the designing of drug delivery systems and medical implants. So the main aim of the present work is to develop a simple mathematical model to represent the complete degradation of PLA implants.P aeruginosa is a leading pathogen that causes nosocomial pneumonia, bloodstream infections, and urinary tract infections in intensive care units. Infections caused by P. aeruginosa are associated with significant morbidity and mortality. The organism exhibits a high level of intrinsic resistance and only a limited number of antimicrobial agents are active against it. Fungal endophytes are receiving increasing attention by natural product chemists due to their diverse and structurally unprecedented compounds which make them interesting candidates for drug discovery. In the present study, a novel endophytic fungus Alternaria alternata was isolated from the medicinal plant Vitex negundo L. Extracts of Alternaria alternata were obtained using hexane, ethyl acetate and methanol solvents. The fungal extracts exhibited an effective antimicrobial activity against bacterial and fungal strains. The extracts were also analyzed for antibacterial activity against ofloxacin, ciprofloxacin and cephotaxaime resistant P. aeruginosa strains (1-8). The ethyl acetate extract showed an effective antibacterial activity against P. aeruginosa strain 7 with minimal inhibitory concentration of 40 μg/ mL. The synergistic action of endophytic fungal extract with antibiotics such as ciprofloxacin and cephotaxime was observed against P. aeruginosa strains 1, 3 and 7. These results clearly indicated that the metabolite of endophytic fungus Alternaria alternata is a potential source for new antibiotic compound. Bioactive metabolites of Alternaria alternata against multidrug resistant Pseudomonas aeruginosa

Design; Synthesis and Antihypertensive activity of 4'-(2-{2-[(2-chloro-benzylidene)-amino]-phenyl}-5-nitro-benzoimidazol-1-ylmethyl)] biphenyl-2-carboxylic acid

In the present study, a series of 4`-(2-{2-[(2-chloro-benzylidene)-amino]-phenyl}-5-nitro-benzoimidazol-1-ylmethyl)] biphenyl-2-carboxylic acid derivatives are synthesized by A one-step coupling of substituted benzimidazoles with biphenyl carboxylic moiety mediated by potassium carbonate is described. The biphenyl carboxylic moiety was prepared from 9-H-fluorenone and substituted benzimidazoles were synthesized from o-phenylenediamine with anthranilic acid. Keywords: Benzimidazoles, biphenyl-2-carboxylic acid, angiotensin II, hypertension