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Uddin R.,University of Karachi | Lodhi M.U.,University of Karachi | Ul-Haq Z.,University of Karachi | Ul-Haq Z.,Heidelberg Institute for Theoretical Studies HITS gGmbH
Chemical Biology and Drug Design | Year: 2012

Methicillin resistant Staphylococcus aureus has become a major health concern and it requires new therapeutic agents. Staphylococcus aureus Sortase A enzyme contributes in adherence of bacteria with the cell wall of host cell; consequently, inhibition of S. aureus Sortase A by small molecules could be employed as potential antibacterial agents against methicillin resistant S. aureus. Current study focused on the identification of 3D pharmacophoric features within a series of rhodanine, pyridazinone, and pyrazolethione analogs as S. aureus Sortase A inhibitors. Pharmacophore model was constructed employing representative molecules using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database. The identified pharmacophoric points were then utilized to create alignment hypothesis for three-dimensional quantitative structure-activity relationships. Outcome of comparative molecular field analysis and comparative molecular similarity indices analysis experiments were in good agreement (comparative molecular field analysis: q 2=0.562 and r 2=0.995, comparative molecular similarity indices analysis: q 2=0.549 and r 2=0.978) and capable of explaining the variance in biological activities coherently with respect to the structural features of compounds. The results were also found in concurrence with the outcome of pharmacophoric features. © 2012 John Wiley & Sons A/S.

Kiefer M.,University of Heidelberg | Schmickl R.,University of Heidelberg | Schmickl R.,Academy of Sciences of the Czech Republic | German D.A.,University of Heidelberg | And 8 more authors.
Plant and Cell Physiology | Year: 2014

The Brassicaceae family (mustards or crucifers) includes Arabidopsis thaliana as one of the most important model species in plant biology and a number of important crop plants such as the various Brassica species (e.g. cabbage, canola and mustard). Moreover, the family comprises an increasing number of species that serve as study systems in many fields of plant science and evolutionary research. However, the systematics and taxonomy of the family are very complex and access to scientifically valuable and reliable information linked to species and genus names and its interpretation are often difficult. BrassiBase is a continuously developing and growing knowledge database (http://brassibase.cos.uni-heidelberg.de) that aims at providing direct access to many different types of information ranging from taxonomy and systematics to phylo-and cytogenetics. Providing critically revised key information, the database intends to optimize comparative evolutionary research in this family and supports the introduction of the Brassicaceae as the model family for evolutionary biology and plant sciences. Some features that should help to accomplish these goals within a comprehensive taxonomic framework have now been implemented in the new version 1.1.9. A 'Phylogenetic Placement Tool' should help to identify critical accessions and germplasm and provide a first visualization of phylogenetic relationships. The 'Cytogenetics Tool' provides in-depth information on genome sizes, chromosome numbers and polyploidy, and sets this information into a Brassicaceae-wide context. © 2013 The Author.

Stamatakis A.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Izquierdo-Carrasco F.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Izquierdo-Carrasco F.,Exelixis
Briefings in Bioinformatics | Year: 2011

Verification in phylogenetics represents an extremely difficult subject. Phylogenetic analysis deals with the reconstruction of evolutionary histories of species, and as long as mankind is not able to travel in time, it will not be possible to verify deep evolutionary histories reconstructed with modern computational methods. Here, we focus on two more tangible issues that are related to verification in phylogenetics (i) the inference of support values on trees that provide some notion about the 'correctness' of the tree within narrow limits and, more importantly; (ii) issues pertaining to program verification, especially with respect to codes that rely heavily on floating-point arithmetics. Program verification represents a largely underestimated problem in computational science that can have fatal effects on scientific conclusions. © The Author 2011. Published by Oxford University Press.

Kokh D.B.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Corni S.,National Research Council Italy | Winn P.J.,University of Birmingham | Hoefling M.,Ludwig Maximilians University of Munich | And 2 more authors.
Journal of Chemical Theory and Computation | Year: 2010

In order to study protein-inorganic surface association processes, we have developed a physics-based energy model, the ProMetCS model, which describes protein-surface interactions at the atomistic level while treating the solvent as a continuum. Here, we present an approach to modeling the interaction of a protein with an atomically flat Au(111) surface in an aqueous solvent. Protein-gold interactions are modeled as the sum of van der Waals, weak chemisorption, and electrostatic interactions, as well as the change in free energy due to partial desolvation of the protein and the metal surface upon association. This desolvation energy includes the effects of water-protein, water-surface, and water-water interactions and has been parametrized using molecular dynamics (MD) simulations of water molecules and a test atom at a gold-water interface. The proposed procedure for computing the energy terms is mostly grid-based and is therefore efficient for application to long-time simulations of protein binding processes. The approach was tested for capped amino acid residues whose potentials of mean force for binding to a gold surface were computed and compared with those obtained previously in MD simulations with water treated explicitly. Calculations show good quantitative agreement with the results from MD simulations for all but one amino acid (Trp), as well as correspondence with available experimental data on the adhesion properties of amino acids. © 2010 American Chemical Society.

Kokh D.B.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Wade R.C.,Heidelberg Institute for Theoretical Studies HITS gGmbH | Wenzel W.,Karlsruhe Institute of Technology
Wiley Interdisciplinary Reviews: Computational Molecular Science | Year: 2011

Protein structural flexibility plays a critical role in receptor-ligand binding processes and should be considered in computational drug design. However, the treatment of protein conformational changes is still a major challenge because it is associated with a large increase in the conformational space that needs to be sampled and requires highly accurate scoring functions that incorporate the receptor reorganization energy. A number of different approaches have been proposed recently to address this problem. Most of them have been shown to be successful in reproducing the correct docking pose of known ligands, but their benefit regarding enrichment, affinity prediction, and screening of large molecular libraries is less clear. Here, we review current methodologies to treat receptor conformational changes in structure-based docking procedures, and show their impact on the accuracy of docking and scoring. We also discuss pitfalls and limitations of state-of-the-art flexible-receptor docking strategies and perspectives for their improvement. © 2011 John Wiley & Sons, Ltd.

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