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Summary: The non‐specific lipid transfer proteins (nsLTPs) are multifunctional seed proteins engaged in several different physiological processes. The nsLTPs are stabilized by four disulfide bonds and exhibit a characteristic hydrophobic cavity, which is the primary lipid binding site. While these proteins are known to transfer lipids between membranes, the mechanism of lipid transfer has remained elusive. Four crystal structures of nsLTP from Solanum melongena, one in the apo‐state and three myristic acid bound states were determined. Among the three lipid bound states, two lipid molecules were bound on the nsLTP surface at different positions and one was inside the cavity. The lipid‐dependent conformational changes leading to opening of the cavity were revealed based on structural and spectroscopic data. The surface‐bound lipid represented a transient intermediate state and the lipid ultimately moved inside the cavity through the cavity gate as revealed by molecular dynamics simulations. Two critical residues in the loop regions played possible 'gating' role in the opening and closing of the cavity. Antifungal activity and membrane permeabilization effect of nsLTP against Fusarium oxysporum suggested that it could possibly involve in bleaching out the lipids. Collectively, these studies support a model of lipid transfer mechanism by nsLTP via intermediate states. Significance Statement: A model of lipid transfer mechanism of nsLTP from Solanum melongena has been proposed through intermediate crystal structures with lipid bound at different sites. [ABSTRACT FROM AUTHOR]

Abstract: Molecular docking, free energy calculation and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 3,5-diaminoindazoles, imidazo(1,2-b)pyridazines and triazolo(1,5-a) pyridazines series of Cyclin-dependent kinase (CDK2) inhibitors. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviations (RMSDs). We found different binding sites namely catalytic, inhibitory phosphorylation, cyclin binding and CKS-binding site of the CDK2 contributing towards the binding of these compounds. Moreover, correlation between free energy of binding and biological activity yielded a statistically significant correlation coefficient. Finally, three representative protein–ligand complexes were subjected to molecular dynamics simulation to determine the stability of the predicted conformations. The low value of the RMSDs between the initial complex structure and the energy minimized final average complex structure suggests that the derived docked complexes are close to equilibrium. We suggest that the phenylacetyl type of substituents and cyclohexyl moiety make the favorable interactions with a number of residues in the active site, and show better inhibitory activity to improve the pharmacokinetic profile of compounds against CDK2. The structure-based drug design strategy described in this study will be highly useful for the development of new inhibitors with high potency and selectivity. [Copyright &y& Elsevier]

Cyclin-dependent kinases (CDKs) are core components of the cell cycle machinery that govern the transition between phases during cell cycle progression. Abnormalities in CDKs activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Their inhibitors have entered in clinical trials to treat cancer. Very recently, Heathcote et al. (J. Med. Chem. 2010, 53:8508-8522) have found a ligand BS194 that has a high affinity with CDK2 (IC50 = 3 n m) but shows low affinity with CDK1 (IC50 = 30 n m). To understand the selectivity, we used homology modeling, molecular docking, molecular dynamics, and free-energy calculation to analyze the interactions. A rational three-dimensional model of the CDK1/BS194 complex is built. We found that Leu83 is a key residue that recognizes BS194 more effectively with CDK2 with good binding free energies rather than CDK1. Energetic analysis reveals that van der Waals interaction and non-polar contributions to solvent are favorable in the formation of complexes and amine group of the ligand, which plays a crucial role for binding selectivity between CDK2 and CDK1. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Half maximal inhibitory concentration (IC50) value measures the effectiveness of compound inhibition towards biological or biochemical utility. Quantitative measure indicates the quantity required for particular inhibitor to inhibit a given biological process (i.e. an enzyme, cell, cell receptor or microorganism) by half. Occasionally, it is also converted to the pIC50 scale (-log IC50), in which higher values indicate exponentially greater potency. These are the experimental values which are predicted and coded in Nanomolar (nM-10-9) and micromolar (μM- 10-6 ). These IC50 values differs in wide range of molecules. So, there are Varity of ranges of applications in molecular modeling techniques especially 3D-QSAR, CoMFA, CoMSIA, Pharmacophore Mapping and many more applications. So, to predict the narrow value from the experimental value, the successful formula is described here to calculate the pIC50 value. As of now, no tool available as open source software to provide the value of pIC50 from IC50 values as pIC50 calculator. In this work we developed the tool for the prediction of pIC50 values from the IC50 in nanomolar and micromolar using the JavaScript programming language, which is available at the Sanjeevslab webpage: http://www.skysanjeev.110mb.com/ index.php?p=1_7_Tools [ABSTRACT FROM AUTHOR]

Introduction: There are several advantages of performing tympanoplasty under Monitored Anaesthesia Care (MAC) and Dexmedetomidine is a good sedative-analgesic for MAC. Aim: To compare the analgesic and sedative efficacy of two different loading doses of dexmedetomidine for tympanoplasty under MAC. Materials and Methods: After taking ethical committee approval, patients were allocated into two groups of 40 each. Group I and Group II patients received injection dexmedetomidine at a loading dose of 1.0 μg/kg and 0.5 μg/kg respectively over 10 min followed immediately by a continuous infusion of 0.4μg/ kg/h. Degree of sedation and pain intensity were assessed using Ramsay Sedation Score (RSS) and Visual Analogue Scale (VAS) respectively. Total rescue doses of Fentanyl and Midazolam as well as surgeon and patient satisfaction scores (Numerical Rating Scale NRS 0-10) were noted. Student t-test, paired t-test and chi-square test were used for statistical analysis. Results: Requirement of higher rescue doses of Fentanyl was more in Group II (100%) as compared to Group I (15.00%) (Z=61.760;p<0.001) and that of Midazolam was also more in Group II (92.50%) as compared to Group I (2.50%) (Z=65.234; p<0.001). Surgeon Satisfaction score was higher in Group I (8.75±0.54) than Group II (6.95±0.50) (Z=7.784;p<0.001). Patient Satisfaction score was also higher in Group I (8.70±0.56) than Group II (6.28±0.60) (Z=7.914;p<0.001).No postoperative complication was seen in any group. Conclusion: A loading dose of 1 μg/kg of dexmedetomidine over 10 min provides better sedation, analgesia, patient satisfaction and surgeon satisfaction than 0.5 μg/kg over 10 min without causing any per-operative problem and seems to be a safe and effective primary sedative technique for tympanoplasty under MAC. [ABSTRACT FROM AUTHOR]

Binding MOAD is a database of protein–ligand complexes and their affinities with many structured relationships across the dataset. The project has been in development for over 20 years, but now, the time has come to bring it to a close. Currently, the database contains 41,409 structures with affinity coverage for 15,223 (37%) complexes. The website BindingMOAD.org provides numerous tools for polypharmacology exploration. Current relationships include links for structures with sequence similarity, 2D ligand similarity, and binding-site similarity. In this last update, we have added 3D ligand similarity using ROCS to identify ligands which may not necessarily be similar in two dimensions but can occupy the same three-dimensional space. For the 20,387 different ligands present in the database, a total of 1,320,511 3D-shape matches between the ligands were added. Examples of the utility of 3D-shape matching in polypharmacology are presented. Finally, plans for future access to the project data are outlined. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer has high incidence in northeastern India; mortality too is high as the disease is often diagnosed late. Numerous studies have shown the role of sonic hedgehog (shh) in different cancers, an important ligand of the hedgehog signaling pathway.Aim: This study was carried out to evaluate the shh gene mutations in gallbladder cancer patients.Methods: PCR-SSCP was performed for shh gene in 50 samples each of gallbladder cancer, cholelithiasis, and control. The samples showing aberration in banding pattern were sequenced.Results: Variation in banding pattern was observed in 20% gallbladder cancer cases, 10% in cholelithiasis, and none of the control (χ 2 = 11.111; p < 0.05). Sequencing results revealed seven novel point mutations in GBC cases. These novel mutations were found to be associated with histopathology (p < 0.05) and stage (p < 0.05) of gallbladder cancer.Conclusion: This study reveals several novel individual and repetitive mutations of shh gene in GBC and cholelithiasis samples that may be used as diagnostic markers for gallbladder carcinogenesis. [ABSTRACT FROM AUTHOR]

Determination of sex constitutes the most important element during the identification process of human skeletal remains. Several sex-specific features of human skeleton have been exploited for sex determination with varying reliability. This study aims to obtain sexual dimorphic standards for ulnae of the north Indian population. Eight measurements were obtained on a sample of 106 ulnae (males-80, females-26) in the age range of 25-65 years. The sexual dimorphism index and demarking points were calculated for all the variables. The data were then subjected to stepwise and direct discriminant function analysis. The best discriminator of sex was the maximum length (84.9%) followed by radial notch width (84%). In stepwise analysis, these two variables were selected and provided an accuracy of 88.7% (M-87.5%, F-92.3%). The proximal end provided a classification rate of 81.1% (M-80%, F-84.6%) with selection of the notch length and olecranon width. [ABSTRACT FROM AUTHOR]

Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to N-methyl pyrimidones as HIV-1 integrase inhibitors. Based on the ligand-based pharmacophore model, we got 5-point pharmacophore model AADDR, with two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R). The generated pharmacophore-based alignment was used to derive a predictive atom-based 3D-QSAR model for the training set ( r2 == 0.92, SD == 0.16, F == 84.8, N == 40) and for test set ( Q2 == 0.71, RMSE == 0.06, Pearson R == 0.90, N == 10). From these results, AADDR pharmacophore feature was selected as best common pharmacophore hypothesis, and atom-based 3D-QSAR results also support the outcome by means of favourable and unfavourable regions of hydrophobic and electron-withdrawing groups for the most potent compound 30. These results can be useful for further design of new and potent HIV-1 IN inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: It is suggested that Salmonella typhi resides mostly in hepatobiliary system especially in gallbladder in chronic typhoid carriers. It is not very clear whether in gallbladder lumen or on its wall or in liver. However, we had been successful in detecting S. typhi in liver by PCR targeting flagellin gene sequences. Therefore, in the present study, we tried to isolate the bacterium from liver tissue collected from dead bodies brought for post mortem examination. We could isolate S. typhi in 2 of 20 such liver tissues examined by using conventional isolation techniques. The isolates were identified by routine phenotypic characters and were confirmed by amplification and sequencing of two conserved genes i.e. 16S rDNA and flagellin (fliC) gene followed by blasting on www.ncbi.nlm.nih.gov. [Copyright &y& Elsevier]

A letter to the editor is presented concerning the potential of Salmonella Typhi to primarily reside in the liver of chronic typhoid patients.