Current Issue : July - September Volume : 2013 Issue Number : 3 Articles : 5 Articles
In the current era of high-throughput drug discovery and development,\r\nmolecular modeling has become an indispensable tool for identifying, optimizing and\r\nprioritizing small-molecule drug candidates. The required background in computational\r\nchemistry and the knowledge of how to handle the complex underlying protocols,\r\nhowever, might keep medicinal chemists from routinely using in silico technologies. Our\r\nobjective is to encourage those researchers to exploit existing modeling technologies more\r\nfrequently through easy-to-use graphical user interfaces. In this account, we present two\r\ninnovative tools (which we are prepared to share with academic institutions) facilitating\r\ncomputational tasks commonly utilized in drug discovery and development: (1) the\r\nVirtualDesignLab estimates the binding affinity of small molecules by simulating and\r\nquantifying their binding to the three-dimensional structure of a target protein; and (2) the\r\nMD Client launches molecular dynamics simulations aimed at exploring the\r\ntime-dependent stability of ligandââ?¬â??protein complexes and provides residue-based\r\ninteraction energies. This allows medicinal chemists to identify sites of potential\r\nimprovement in their candidate molecule. As a case study, we present the application of\r\nour tools towards the design of novel antagonists for the FimH adhesin....
Hydrotropy is a phenomenon where the presence of a large quantity of one solute enhances the solubility of another solute. The\r\nmechanism of this phenomenon remains a topic of debate.This study employed molecular dynamics simulation to investigate the\r\nhydrotropic mechanism of a series of urea derivatives, that is, urea (UR), methylurea (MU), ethylurea (EU), and butylurea (BU).\r\nA poorly water-soluble compound, nifedipine (NF), was used as the model solute that was solubilized. Structural, dynamic, and\r\nenergetic changes upon equilibrationwere analyzed to supply insights to the solubilization mechanism.Thestudy demonstrated that\r\nNF and urea derivatives underwent significant nonstoichiometric molecular aggregation in the aqueous solution, a result consistent\r\nwith the self-aggregation of urea derivatives under the same conditions. The analysis of hydrogen bonding and energy changes\r\nrevealed that the aggregation was driven by the partial restoration of normal water structure.The energetic data also suggested that\r\nthe promoted solubilization of NF is favored in the presence of urea derivatives.While the solutes aggregated to a varying degree,\r\nthe systems were still in single-phase liquid state as attested by their active dynamics....
Lung cancer is the leading cause of death among malignant diseases in humans worldwide. In the last\r\ndecade development of new targeted drugs for the treatment of non-small cell lung cancer proved to be a\r\npromising approach to prolong the otherwise very poor prognosis of patients with advanced UICC stages.\r\nEpidermal growth factor receptor (EGFR) has been in the focus of this lung cancer science and specific activating\r\nmutations are eligible for the treatment with specific tyrosine kinase inhibitors like gefitinib or erlotinib. Beside\r\ntypical deletions in exon 19 and point mutations in exons 18 and 21 several insertions in exon 19 have been\r\ndescribed and attributed activating properties as well. This is the first European and overall the 5th description in\r\nEnglish literature of one of these specific insertions. To elucidate its structural changes leading to the activating\r\nproperties we performed molecular modeling studies. These revealed conformational and electrostatic force field\r\nchanges in the kinase domain of EGFR. To not miss uncommon mutations thorough and precise characterization of\r\nEGFR hotspots, i. e. at least exons 18, 19 and 21, should therefore be conducted to provide best medical care and\r\nto offer lung cancer patients appropriate cancer treatment....
The interaction of transresveratrol (TRES) with bovine serum albumin (BSA) has been investigated by ultraviolet-visible,\r\nfluorescence, Fourier transform infrared spectroscopic methods and molecular modeling techniques. The fluorescence results\r\nshow that the intrinsic fluorescence of BSA is quenched by TRES through a static quenching procedure. The binding constants\r\nof TRES with BSA at 292, 297 and 302K are calculated as 10.22 Ã?â?? 104, 8.71 Ã?â?? 104, and 7.59 Ã?â?? 104 Lmol-1, respectively, and\r\ncorresponding numbers of binding sites are approximately equal to unity.The thermodynamic parameters ?H and ?S are estimated\r\nto be -21.82 kJmol-1 and .15 Jmol-1 K-1, which indicates that the interaction of TRES with BSA is driven mainly by hydrophobic\r\nforces and there are also hydrogen bonds and electrostatic interactions. The competitive experiments suggest that the binding site\r\nof TRES to BSA is probably located on site II. The results of infrared spectra show that the binding of TRES with BSA leads to\r\nconformational changes of BSA, and the binding stabilizes the ??-helix and ??-sheet at the cost of a corresponding loss in the ??-turn\r\nstructure of BSA. The results of molecular modeling calculation clarify the binding mode and the binding sites which are in good\r\naccordance with the experiment results....
Background: With the progress of nanotechnology, one frequently has to model biological macromolecules\r\nsimultaneously with nano-objects. However, the atomic structures of the nano objects are typically not available or\r\nthey are solid state entities. Because of that, the researchers have to investigate such nano systems by generating\r\nmodels of the nano objects in a manner that the existing software be able to carry the simulations. In addition, it\r\nshould allow generating composite objects with complex shape by combining basic geometrical figures and\r\nembedding biological macromolecules within the system.\r\nResults: Here we report the Protein Nano-Object Integrator (ProNOI) which allows for generating atomic-style\r\ngeometrical objects with user desired shape and dimensions. Unlimited number of objects can be created and\r\ncombined with biological macromolecules in Protein Data Bank (PDB) format file. Once the objects are generated,\r\nthe users can use sliders to manipulate their shape, dimension and absolute position. In addition, the software\r\noffers the option to charge the objects with either specified surface or volumetric charge density and to model\r\nthem with user-desired dielectric constants. According to the user preference, the biological macromolecule atoms\r\ncan be assigned charges and radii according to four different force fields: Amber, Charmm, OPLS and PARSE. The\r\nbiological macromolecules and the atomic-style objects are exported as a position, charge and radius (PQR) file, or\r\nif a default dielectric constant distribution is not selected, it is exported as a position, charge, radius and epsilon\r\n(PQRE) file. As illustration of the capabilities of the ProNOI, we created a composite object in a shape of a robot,\r\naptly named the Clemson Robot, whose parts are charged with various volumetric charge densities and holds the\r\nbarnase-barstar protein complex in its hand.\r\nConclusions: The Protein Nano-Object Integrator (ProNOI) is a convenient tool for generating atomic-style nano\r\nshapes in conjunction with biological macromolecule(s). Charges and radii on the macromolecule atoms and the\r\natoms in the shapes are assigned according to the user�s preferences allowing various scenarios of modeling. The\r\ndefault output file is in PQR (PQRE) format which is readable by almost any software available in biophysical field. It\r\ncan be downloaded from: http://compbio.clemson.edu/downloadDir/ProNO_integrator.tar.gz...
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