Current Issue : October - December Volume : 2013 Issue Number : 4 Articles : 6 Articles
Polycystin-1 is a large transmembrane protein, which, whenmutated, causes autosomal dominant polycystic kidney disease, one of\r\nthe most common life-threatening genetic diseases that is a leading cause of kidney failure.The REJ (receptor for egg lelly) module\r\nis a major component of PC1 ectodomain that extends to about 1000 amino acids. Many missense disease-causing mutations map\r\nto this module; however, very little is known about the structure or function of this region. We used a combination of homology\r\nmolecularmodeling, protein engineering, steered molecular dynamics (SMD) simulations, and single-molecule force spectroscopy\r\n(SMFS) to analyze the conformation and mechanical stability of the first ~420 amino acids of REJ. Homology molecular modeling\r\nanalysis revealed that this regionmay contain structural elements that have an FNIII-like structure, which we named REJd1, REJd2,\r\nREJd3, and REJd4.We found that REJd1 has a higher mechanical stability than REJd2 (~190 pN and 60 pN, resp.). Our data suggest\r\nthat the putative domains REJd3 and REJd4 likely do not form mechanically stable folds. Our experimental approach opens a new\r\nway to systematically study the effects of disease-causing mutations on the structure and mechanical properties of the REJ module\r\nof PC1....
In this study, an attempt was made to develop the docking studies of series of substituted thiazole analogs with cyclo-oxygenase-2 (COX-2) inhibitor (PDB-code 1CX2) to identify potential candidates with minimum dock score for anti-inflammatory activity. Molecular docking analysis was carried out to better understand the interactions between 1CX2 target and inhibitors in this series. Hydrophobic and hydrogen bond interactions lead to identification of active binding sites. A set of eleven novel substituted thiazole analogs with anti-inflammatory activity was subjected to the two dimensional quantitative structure activity relationships (2D QSAR) studies using MDS 4.0. Drug designing module with various combinations of thermodynamic, electronic and spatial descriptors. 2D QSAR was performed using Multiple Regression (MR), Principal Component Regression (PCR), partial least squares regression (PLS) method. The best 2D-QSAR model (r2 = 0.99, Fisher test value F=4549.12, r2 se =0.25) has acceptable statistical quality and predictive potential as indicated by the value of cross validated squared correlation coefficient (q2=0.92) by stepwise forward multiple regression (model-1), (r2 =0.9828, F =171.5722, r2 se =2.2614, q2 = -0.1954) by stepwise forword partial least squares regression (model-2), ( r2 =0.9825, F = 168.6592, r2 se =1.0488, q2 = 0.9454) by genetic algorithm principle component regression (model-3). From this 3 model, it seems to be clear that chiV5chain, chiV4pathCluster, T_2_N_2, T_2_S_0, T_2_S_7, T_C_N_5, T_T_O_2 contribute positively and 4pathClusterCount contribute negatively for anti-inflammatory activity. Thus this validated model brings important structural insight to aid the design of novel anti-inflammatory agent with potent compound....
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The hydrophilic/hydrophobic nature of cellulose is based on its structural anisotropy. Cellulose chains are arranged in a parallel\r\nmanner and are organized in sheets stabilized by interchain OHââ?¬â??O hydrogen bonds, whereas the stacking of sheets is stabilized by\r\nboth van derWaals (vdW) dispersion forces and weak CHââ?¬â??O hydrogen bonds. Cellulose has a strong affinity to itself andmaterials\r\ncontaining hydroxyls, especiallywater. Based on the preponderance of hydroxyl functional groups, cellulose polymer is very reactive\r\nwith water. Water molecular smallness promotes the reaction with the cellulose chains and immediately formed hydrogen bonds.\r\nBesides that, vdW dispersion forces play an important role between these two reactive entities. They stabilize the cellulose structure\r\naccording to the considerable cohesive energy in the cellulose network. Hydrogen bonding, electrostatic interactions, and vdW\r\ndispersion forces play an important role in determining the cellulose crystal structure during the cellulose-water interactions. As a\r\nresult of these interactions, the volume of cellulose undergoes a meaningful change expressed not only by an exponential growth\r\nin amorphous regions, but also by an expansion in nanocrystalline regions. In addition, the volume change is associated with the\r\nswelling material expressed as a weight gain of the cellulose polymer.Molecular modeling using AccelrysMaterials Studio allowed\r\nus to open a new horizon and is helpful for understanding cellulose-water interactions....
Cellulose chains are linear and aggregation occurs via both intra- and intermolecular hydrogen bonds.Cellulose has a strong affinity\r\nto itself and toward materials containing hydroxyls groups. Based on the preponderance of hydroxyl functional groups, cellulose is\r\nvery reactive with water. At room temperature, cellulose chains will have at least a monomolecular layer of water associated to it.\r\nTheformation of hydrogen bonds at the cellulose/water interface is shown to depend essentially on the adsorption site, for example,\r\nthe equatorial hydroxyls or OH moieties pointing outward from the cellulose chains. The vdWforces also contribute significantly\r\nto the adsorption energy.They are a considerable cohesive energy into the cellulose network. At the surface of the cellulose chains,\r\nmany intermolecular hydrogen bonds of the cellulose chains are lost. However, they are compensated by hydrogen bonds with\r\nwater molecules. Electronic clouds can be distorted and create electrostatic dipoles. The large antibonding electron cloud that\r\nexists around the glucosidic bonds produces an induced polarization at the approach of water molecules. The electron cloud can\r\nbe distorted and create an electrostatic dipole. It applies to the total displacement of the atoms within the material. Orbitals play a\r\nspecial role in reaction mechanism. Hydrophilic/hydrophobic nature of cellulose is based on its structural anisotropy. Cellulosewater\r\ninteractions are exothermic reactions. These interactions may occur spontaneously and result in higher randomness of the\r\nsystem. They are denoted by a negative heat flow (heat is lost to the surroundings). Energy does not need to be inputted in order\r\nfor cellulose-water interactions to occur....
Topomer CoMFA studies have gained importance due to their good predictability as a CADD tool. Azetidinone derivatives show good antimitotic activity since they act as conformationally restricted analogues of combrestatin A4. This study aims to develop Topomer CoMFA model to search new substitutions at F1 fragment of azetidinone nucleus. We have selected a series of 32 compounds showing activity against MCF-7 cell lines. A topomer CoMFA model has been developed with q2 and r2 as 0.655 and 0.906 respectively. The compounds have been segmented into 3 fragments. Various substitutions at R4, R5 and R6 of F1 fragment were optimized. The best 7 predicted fragments with topomer scores better than the test series have been suggested. This study will help to develop newer molecules with better activity. Topomer CoMFA clearly signifies its importance in the field of new drug discovery by predicting possible replacements in place of original functionality, which has been shown in this article....
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