Current Issue : January - March Volume : 2015 Issue Number : 1 Articles : 7 Articles
Topoisomerase is a critical enzyme vital for DNA replication and consequently playing a pivotal role in oncology. Being a validated target in anticancer drug discovery and having a well-established link between the higher enzyme activity and malignancy, topoisomerase has become an excellent target to inhibit. In this study, a series of 21 topoisomerase I inhibitors, having Indenoisoquinoline ring system as the parent scaffold, was taken for molecular modeling. Molecular characteristics such as steric, electrostatic and hydrogen bonding and their influence on afforded biological activity were established using 3D QSAR techniques; comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Top1 inhibition and indenoisoquinoline ring may make these molecules potential molecules in oncology. A statistically comprehensive and robust model was developed having significant r2 and r2pred values giving better insights of spatially focal regions around the scaffold which directly have an effect on the degree of biological activity. Segregating the series into test and training sets allowed calculations authenticating the predictive ability of the developed model. Coloured contour maps and statistical analyses might provide substantial assistance in developing better molecules with similar structures in future....
Purpose: G protein-coupled receptors (GPCRs) are a superfamily of membrane proteins of vast pharmaceutical\ninterest. Here, we describe a graph theory-based analysis of the structure of the ?2 adrenergic receptor (?2 AR), a\nprototypical GPCR. In particular, we illustrate the network of direct and indirect interactions that link each amino\nacid residue to any other residue of the receptor.\nMethods: Networks of interconnected amino acid residues in proteins are analogous to social networks of\ninterconnected people. Hence, they can be studied through the same analysis tools typically employed to analyze\nsocial networks ââ?¬â?? or networks in general ââ?¬â?? to reveal patterns of connectivity, influential members, and dynamicity.\nWe focused on the analysis of closeness-centrality, which is a measure of the overall connectivity distance of the\nmember of a network to all other members.\nResults: The residues endowed with the highest closeness-centrality are located in the middle of the seven\ntransmembrane domains (TMs). In particular, they are mostly located in the middle of TM2, TM3, TM6 or TM7, while\nfewer of them are located in the middle of TM1, TM4 or TM5. At the cytosolic end of TM6, the centrality detected\nfor the active structure is markedly lower than that detected for the corresponding residues in the inactive structures.\nMoreover, several residues acquire centrality when the structures are analyzed in the presence of ligands. Strikingly,\nthere is little overlap between the residues that acquire centrality in the presence of the ligand in the blocker-bound\nstructures and the agonist-bound structures.\nConclusions: Our results reflect the fact that the receptor resembles a bow tie, with a rather tight knot of closely\ninterconnected residues and two ends that fan out in two opposite directions: one toward the extracellular space,\nwhich hosts the ligand binding cavity, and one toward the cytosol, which hosts the G protein binding cavity. Moreover,\nthey underscore how interaction network is by the conformational rearrangements concomitant with the activation of\nthe receptor and by the presence of agonists or blockers....
Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is major resistant and inhibitor factor of TRAIL mediated apoptosis in cancer cells. Generally cFLIP is over expressed in all cancer cells and act as anti apoptotic agent, hence it became one of the important targets for cancer therapy. Fungal peptides are having very good pharmaceutical value and reported for various treatment. In present investigation, we described the binding affinity of fungal peptides with cFLIP. Four fungal peptides Pneumocandin B0, Aureobasidin G, WF 11899A, Echinocandin B structures were retrieved pubchem database and cFLIP protein structure was retrieved from Protein Data Bank. Docking studies were carryout by using Hex 8.0.0. Their interactions and binding interface were identified by Ligplot 1.4.5. All four fungal peptides are having binding affinity with cFLIP, among them Pneumocandin B0 showed highest binding energy value of -455.18, having two hydrogen and nine hydrophobic bonds with cFLIP. Whereas, Aureobasidin G exposed energy value of -414.96, Ligpolt analysis showed three hydrogen and seven hydrophobic bonds. WF 11899A binding energy was found to be -377.18, one hydrogen and eight hydrophobic bonds were identified with cFLIP interaction. Echinocandin B was having least binding affinity -342.59 and having only eight hydrophobic bonds. Further in-vitro and in-vivo study is needed to confirm their inhibitor effect on cFLIP....
Theinteraction of patulin with human serum albumin (HSA) was studied in vitro under normal physiological conditions.The study\nwas performed using fluorescence, ultraviolet-visible spectroscopy (UV-Vis), circular dichroism (CD), atomic force microscopy\n(AFM), and molecular modeling techniques. The quenching mechanism was investigated using the association constants, the\nnumber of binding sites, and basic thermodynamic parameters. A dynamic quenching mechanism occurred between HSA and\npatulin, and the binding constants (K) were 2.60 Ã?â?? 104, 4.59 Ã?â?? 104, and 7.01 Ã?â?? 104M?1 at 288, 300, and 310 K, respectively. Based\non fluorescence resonance energy transfer, the distance between the HSA and patulin was determined to be 2.847 nm. The ?G0,\n?H0, and ?S0 values across various temperatures indicated that hydrophobic interaction was the predominant binding force. The\nUV-Vis and CD results confirmed that the secondary structure of HSA was altered in the presence of patulin. The AFM results\nrevealed that the individual HSA molecule dimensions were larger after interaction with patulin. In addition, molecular modeling\nshowed that the patulin-HSA complex was stabilized by hydrophobic and hydrogen bond forces. The study results suggested that a\nweak intermolecular interaction occurred between patulin and HSA. Overall, the results are potentially useful for elucidating the\ntoxigenicity of patulin when it is combined with the biomolecular function effect, transmembrane transport, toxicological, testing\nand other experiments....
Purpose: It was shown by several experimental studies that some G protein coupled receptors (GPCR) are sensitive\nto sodium ions. Furthermore, mutagenesis studies or the determination of crystal structures of the adenosine A2A or\n?-opioid receptor revealed an allosteric Na+ binding pocket near to the highly conserved Asp2.50. Within a previous\nstudy, the influence of NaCl concentration onto the steady-state GTPase activity at the human histamine H3 receptor\n(hH3R) in presence of the endogenous histamine or the inverse agonist thioperamide was analyzed. The purpose of the\npresent study was to examine and quantify the Na+-sensitivity of hH3R on a molecular level.\nMethods: To achieve this, we developed a set of equations, describing constitutive activity and the different\nligand-receptor equilibria in absence or presence of sodium ions. Furthermore, in order to gain a better\nunderstanding of the ligand- and Na+-binding to hH3R on molecular level, we performed molecular dynamic\n(MD) simulations.\nResults: The analysis of the previously determined experimental steady-state GTPase data with the set of equations\npresented within this study, reveals that thioperamide binds into the orthosteric binding pocket of the hH3R in absence\nor presence of a Na+ in its allosteric binding site. However, the data suggest that thioperamide binds preferentially into\nthe hH3R in absence of a sodium ion in its allosteric site. These experimental results were supported by MD simulations\nof thioperamide in the binding pocket of the inactive hH3R. Furthermore, the MD simulations revealed two different\nbinding modes for thioperamide in presence or absence of a Na+ in its allosteric site.\nConclusion: The mathematical model presented within this study describes the experimental data regarding the\nNa+-sensitivity of hH3R in an excellent manner. Although the present study is focused onto the Na+-sensitivity\nof the hH3R, the resulting equations, describing Na+- and ligand-binding to a GPCR, can be used for all other\nion-sensitive GPCRs....
In this paper, we concentrated on the docking approach to analyse effective treatment for cancer. Docking studies have been performed on the novel pyrazolo [3,4-d] pyrimidines to explore the structural features responsible for their activity on EGFR kinases. Series of pyrazolo [3,4-d] pyrimidine derivatives compounds were taken from M M Kandeel et al., for anti-tumor activity. SYBYL - X 2.0 software were used for docking. From the docking studies we got 3 best docked compounds....
Introduction. Osteomyelitis is a severe orthopaedic complication which is difficult to diagnose and treat. Previous experimental\nstudies mainly focussed on evaluating osteomyelitis in the presence of an implant or used a sclerosing agent to promote infection\nonset. In contrast, we focused on the longitudinal assessment of a nonimplant related osteomyelitis. Methods. An intramedullary\ntibial infection with S. aureus was established in NZW rabbits. Clinical and haematological infection status was evaluated\nweekly, combined with X-ray radiographs, biweekly injections of calcium binding fluorophores, and postmortem micro-CT.The\ndevelopment of the infection was assessed by micro-PET at consecutive time points using 18F-FDG as an infection tracer. Results.\nThe intramedullary contamination of the rabbit tibia resulted in an osteomyelitis. Haematological parameters confirmed infection\nin mainly the first postoperative weeks (CRP at the first 5 postoperative weeks, leucocyte differentiation at the second and sixth\npostoperative weeks, and ESR on the second postoperative week only), while micro-PET was able to detect the infection from the\nfirst post-operative week onward until the end of the study. Conclusions.This study shows that osteomyelitis in the rabbit can be\ninduced without use of an implant or sclerosing agent.The sequential follow-up indicates that the diagnostic value of each infection\nparameter is time point dependant. Furthermore, fromall parameters used, the diagnostic value of 18F-FDGmicro-PET is themost\nversatile to assess the presence of an orthopaedic infection in this model....
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