Current Issue : October - December Volume : 2015 Issue Number : 4 Articles : 5 Articles
Background: MMP-2 enzyme is a kind of matrix metalloproteinases that digests the denatured collagens and\ngelatins. It is highly involved in the process of tumor invasion and has been considered as a promising target for\ncancer therapy. The structural requirements of an MMP-2 inhibitor are: (1) a functional group that binds the zinc\nion, and (2) a functional group which interacts with the enzyme backbone and the side chains which undergo\neffective interactions with the enzyme subsites.\nMethods: In the present study, a QSAR model was generated to screen new inhibitors of MMP-2 based on\nLââ?¬â??hydroxy tyrosine scaffold. Descriptors generation were done by Hyperchem 8, DRAGON and Gaussian98W\nprograms. SPSS and MATLAB programs have been used for multiple linear regression (MLR) and genetic algorithm\npartial least squares (GA-PLS) analyses and for theoretical validation. Applicability domain of the model was performed\nto screen new compounds. The binding site potential of all inhibitors was verified by structure-based docking according\nto their binding energy and then the best inhibitors were selected.\nResults: The best QSAR models in MLR and GA-PLS were reported, with the square correlation coefficient for\nleave-one-out cross-validation (Q2\nLOO) larger than 0.921 and 0.900 respectively. The created MLR and GA-PLS\nmodels indicated the importance of molecular size, degree of branching, flexibility, shape, three-dimensional\ncoordination of different atoms in a molecule in inhibitory activities against MMP-2.\nThe docking study indicated that lipophilic and hydrogen bonding interactions among the inhibitors and the receptor\nare involved in a ligand-receptor interaction. The oxygen of carbonyl and sulfonyl groups is important for hydrogen bonds\nof ligand with Leu82 and Ala83. R2 and R3 substituents play a main role in hydrogen bonding interactions. R1 is sited in\nthe hydrophobic pocket. Methylene group can help a ligand to be fitted in the lipophilic pocket, so two methylene\ngroups are better than one. The Phenyl group can create a ?-? interaction with Phe86.\nConclusions: The QSAR and docking analyses demonstrated to be helpful tools in the prediction of anti-cancer activities\nand a guide to the synthesis of new metalloproteinase inhibitors based on L-tyrosine scaffold....
In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect\ncoagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective\nand convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is\naimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and post docking optimization\nDISCORE programs. After validation of molecular modeling methods on well-known factor Xa inhibitors the virtual screening of\nNCID iversity and Voronezh State University databases of ready-made low molecular weight species has been carried out. Seventeen\ncompounds selected on the basis of modeling results have been tested experimentally in vitro. It has been found that 12 of them\nshowed activity against factor Xa (IC50 = 1.8ââ?¬â??40 Ã?µM). Based on analysis of the results, the new original compound was synthesized\nand experimentally verified. It shows activity against factor Xa with IC50 value of 0.7 Ã?µM....
Background: Bacopa monnieri Linn. (Plantaginaceae), a well-known medicinal plant, is widely used in traditional\nmedicine system. It has long been used in gastrointestinal discomfort, skin diseases, epilepsy and analgesia. This\nresearch investigated the in vitro antimicrobial activity of Bacopa monnieri leaf extract against Staphylococcus aureus\nand the interaction of possible compounds involved in this antimicrobial action.\nMethods: Non-edible plant parts were extracted with ethanol and evaporated in vacuo to obtain the crude extract.\nA zone of inhibition studies and the minimum inhibitory concentration (MIC) of plant extracts were evaluated\nagainst clinical isolates by the microbroth dilution method. Docking study was performed to analyze and identify\nthe interactions of possible antimicrobial compounds of Bacopa monnieri in the active site of penicillin binding\nprotein and DNA gyrase through GOLD 4.12 software.\nResults: A zone of inhibition studies showed significant (p < 0.05) inhibition capacity of different concentrations of\nBacopa monnieri�s extract against Staphylococcus aureus. The extract also displayed very remarkable minimum\ninhibitory concentrations (?16 ?g/ml) which was significant compared to that (?75 ?g/ml) of the reference\nantibiotic against the experimental strain Staphylococcus aureus. Docking studies recommended that luteolin, an\nexisting phytochemical of Bacopa monnieri, has the highest fitness score and more specificity towards the DNA\ngyrase binding site rather than penicillin binding protein.\nConclusions: Bacopa monnieri extract and its compound luteolin have a significant antimicrobial activity against\nStaphylococcus aureus. Molecular binding interaction of an in silico data demonstrated that luteolin has more\nspecificity towards the DNA gyrase binding site and could be a potent antimicrobial compound....
Leflunomide is a disease-modifying antirheumatic\ndrug with antiinflammatory and immunosuppressive activity\nused for the treatment of psoriatic and rheumatoid arthritis. It\nundergoes rapid metabolization to teriflunomide, a metabolite\nthat is responsible for the biological activity of leflunomide.\nContinuing our investigations on the interactions of biologically\nimportant azahetarenes with the environment, we focused\non leflunomide and its active metabolite, teriflunomide,\nconsidering the interactions teriflunomideââ?¬â??amino acid within\nthe target protein (dihydroorotate dehydrogenase) using density\nfunctional theory, as well as ONIOM techniques. The\nresults of theoretical studies have shown that the interactions\nof teriflunomide with tyrosine and arginine involve principally\nthe amide fragment of teriflunomide. The presence of the internal\nhydrogen bond between (Z)-teriflunomide carbonyl oxygen\nand enolic hydroxyl decreases the interaction strength\nbetween teriflunomide and tyrosine or arginine. Even the E\nisomer of teriflunomide would usually provide a stronger interaction\nteriflunomideââ?¬â?amino acid than the Z isomer with\nthe internal hydrogen bond....
The absorption and emission spectra of three azo\nsulfonamide compounds in different solvents were investigated\ntheoretically by using response functions combined with\ndensity functional theory (DFT), while the solvent effect on\nthe structure and the electronic transitions was determined\nusing the integral equation formalism for the polarizable continuum\nmodel (IEF-PCM). The results show that the applied\ndifferent exchange-correlation functionals can reproduce the\nexperimental values well. DFT calculations of the title compounds\nshowed that the H-bond formed between the solute\nand solvent molecules is one of the major causes of the\nreversible solvatochromism observed in measured spectra.\nThis is due to a better stabilization of the neutral\nform than the zwitterionic form in the polar protic solvents,\nwhich is characteristic of the hypsochromic shift.\nOn the other hand, the molecules considered exhibit a\nmonotonic behavior regarding the polarity of the lowlying\nexcited state (??gââ?¬â??CT) as a function of the solvent\npolarity. This dependence occurs in the case of the positive\nsolvatochromism and confirms the thesis regarding\nthe H-bond soluteââ?¬â??solvent interactions. Theoretically determined\nvalues of the two-photon cross section revealed\nthat the (?OF\n(2) ) shows similar trends with changes\nin ?abs, in contrast to ??OF? values. In conclusion, the\nresults demonstrate that the investigated molecules can\nbe used successfully as fluorochromes in bioimaging....
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