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Gerhard Klebe

Publications and source records attributed to Gerhard Klebe.

65 records · Page 4Linked to original sources
PubMed2002

Docking into knowledge-based potential fields: a comparative evaluation of DrugScore.

A new application of DrugScore is reported in which the knowledge-based pair potentials serve as objective function in docking optimizations. The Lamarckian genetic algorithm of AutoDock is used to search for favorable ligand binding modes guided by DrugScore grids as representations of the protein binding site. The approach is found to be successful in many cases where DrugScore-based re-ranking of already docked ligand conformations does not yield satisfactory results. Compared to the AutoDock scoring function, DrugScore yields slightly superior results in flexible docking.

Algorithms↗
PubMed2002

Development of new hydrogen-bond descriptors and their application to comparative molecular field analyses.

Knowledge-based descriptors extracted from composite crystal-field environments in crystal data have been developed for the description of interaction properties of small molecules. Using SuperStar seven diverse probe atoms have been selected to reflect the most important physicochemical properties. The general application of these descriptors in comparative molecular field analysis has been investigated using a dataset of thermolysin inhibitors, and a comparison to the GRID program has been performed. We especially focused on hydrogen-bond donor and acceptor properties by selecting a carbonyl and amino group as suitable probes. Their performance has been compared to that of the hydrogen-bond descriptors presently implemented in CoMSIA (comparative molecular similarity indices analysis). The newly developed descriptors produced significantly improved statistics for the correlation analyses if they are exclusively applied or, even better, applied in combination with other CoMSIA descriptors. Two methodologically different approaches have been tested to approximate the developed descriptors. Both reduce significantly the required computational efforts in particular for large data sets. The graphical interpretation of the field contributions of hydrogen-bonding properties elucidates additional features compared to those obtained from the original CoMSIA method. They are of valuable support for the design of improved inhibitors.

Databases, Factual↗
PubMed2002

Identification and mapping of small-molecule binding sites in proteins: computational tools for structure-based drug design.

The number of protein structures is currently increasing at an impressive rate. The growing wealth of data calls for methods to efficiently exploit structural information for medicinal and pharmaceutical purposes. Given the three-dimensional (3D) structure of a validated protein target, the identification of functionally relevant binding sites and the analysis ('mapping') of these sites with respect to molecular recognition properties are important initial tasks in structure-based drug design. To address these tasks, a variety of computational tools have been developed. Approaches to identify binding pockets include geometric analyses of protein surfaces, comparisons of protein structures, similarity searches in databases of protein cavities, and docking scans to reveal areas of high ligand complementarity. In the context of binding-site analysis, powerful data mining tools help to retrieve experimental information about related protein-ligand complexes. To identify interaction hot spots, various potential functions and knowledge-based approaches are available for mapping binding regions. The results may subsequently be used to guide virtual screenings for new ligands via pharmacophore searches or docking simulations.

Artificial Intelligence↗
PubMed2002

Loading of tetanus toxoid to biodegradable nanoparticles from branched poly(sulfobutyl-polyvinyl alcohol)-g-(lactide-co-glycolide) nanoparticles by protein adsorption: a mechanistic study.

PURPOSE: Mucosal delivery of vaccine-loaded nanoparticles (NP) is an attractive proposition from an immunologic perspective. Although numerous NP preparation methods are known, sufficient antigen loading of NP remains a challenge. The aim of this study was to evaluate adsorptive loading of NP with a negatively charged surface structure using tetanus toxoid (TT) as a model vaccine. METHODS: Blank NP, consisting of poly(sulfobutyl-polyvinyl alcohol)-g-(lactide-co-glycolide), as well as poly(lactide-co-glycolide) NP were prepared by a solvent displacement technique. The use of polymers with different degrees of substitution resulted in NP with different negative surfaces charges. Adsorption of TT to NP was performed varying to NP surface properties, protein equilibrium concentration, and loading conditions. RESULTS: The protein adsorption was controlled by NP surface properties, and maximum TT adsorption occurred at highly negatively charged NP surfaces. Results from isothermal titration calorimetry and zeta-potential measurement suggest an adsorption process governed by electrostatic interactions. The adsorption followed the Langmuir isotherm in the concentration ranges studied. TT withstood this gentle loading procedure in a nonaggregated, enzyme-linked immunoabsorbant assay-active form. CONCLUSION: The results demonstrate that negatively charged NP consisting of poly(sulfobutyl-polyvinyl alcohol)-g-(lactide-co-glycolide) are suitable for adsorptive loading with TT and may have potential for mucosal vaccination.

Adsorption↗
PubMed2001

Crystal structure of 1-deoxy-D-xylulose-5-phosphate reductoisomerase, a crucial enzyme in the non-mevalonate pathway of isoprenoid biosynthesis.

We have solved the 2.5-A crystal structure of 1-deoxy-D-xylulose-5-phosphate reductoisomerase, an enzyme involved in the mevalonate-independent 2-C-methyl-D-erythritol-4-phosphate pathway of isoprenoid biosynthesis. The structure reveals that the enzyme is present as a homodimer. Each monomer displays a V-like shape and is composed of an amino-terminal dinucleotide binding domain, a connective domain, and a carboxyl-terminal four-helix bundle domain. The connective domain is responsible for dimerization and harbors most of the active site. The strictly conserved acidic residues Asp(150), Glu(152), Glu(231), and Glu(234) are clustered at the putative active site and are probably involved in the binding of divalent cations mandatory for enzyme activity. The connective and four-helix bundle domains show significant mobility upon superposition of the dinucleotide binding domains of the three conformational states present in the asymmetric unit of the crystal. A still more pronounced flexibility is observed for a loop spanning residues 186 to 216, which adopts two completely different conformations within the three protein conformers. A possible involvement of this loop in an induced fit during substrate binding is discussed.

Aldose-Ketose Isomerases↗
PubMedDate not supplied

A 3D QSAR study on a set of dopamine D4 receptor antagonists.

The molecular alignments obtained from a previously reported pharmacophore model have been employed in a three-dimensional quantitative structure-activity relationship (3D QSAR) study, to obtain a more detailed insight into the structure-activity relationships for D(2) and D(4) receptor antagonists. The frequently applied CoMFA method and the related CoMSIA method were used. Statistically significant models have been derived with these two methods, based on a set of 32 structurally diverse D(2) and D(4) receptor antagonists. The CoMSIA and the CoMFA methods produced equally good models expressed in terms of q(2) values. The predictive power of the derived models were demonstrated to be high. Graphical interpretation of the results, provided by the CoMSIA method, brings to light important structural features of the compounds related to either low- or high-affinity D(2) or D(4) antagonism. The results of the 3D QSAR studies indicate that bulky N-substituents decrease D(2) binding, whereas D(4) binding is enhanced. Electrostatically favorable and unfavorable regions exclusive to D(2) receptor binding were identified. Likewise, certain hydrogen-bond acceptors can be used to lower D(2) affinity. These observations may be exploited for the design of novel dopamine D(4) selective antagonists.

Dopamine D2 Receptor Antagonists↗
PubMedDate not supplied

3D QSAR selectivity analyses of carbonic anhydrase inhibitors: insights for the design of isozyme selective inhibitors.

A 3D QSAR selectivity analysis of carbonic anhydrase (CA) inhibitors using a data set of 87 CA inhibitors is reported. After ligand minimization in the binding pockets of CA I, CA II, and CA IV isoforms, selectivity CoMFA and CoMSIA 3D QSAR models have been derived by taking the affinity differences (DeltapKi) with respect to two CA isozymes as independent variables. Evaluation of the developed 3D QSAR selectivity models allows us to determine amino acids in the respective CA isozymes that possibly play a crucial role for selective inhibition of these isozymes. We further combined the ligand-based 3D QSAR models with the docking program AUTODOCK in order to screen for novel CA inhibitors. Correct binding modes are predicted for various CA inhibitors with respect to known crystal structures. Furthermore, in combination with the developed 3D QSAR models we could successfully estimate the affinity of CA inhibitors even in cases where the applied scoring function failed. This novel strategy to combine AUTODOCK poses with CoMFA/CoMSIA 3D QSAR models can be used as a guideline to assess the relevance of generated binding modes and to accurately predict the binding affinity of newly designed CA inhibitors that could play a crucial role in the treatment of pathologies such as tumors, obesity, or glaucoma.

Animals↗
PubMedDate not supplied

Trypsin mutants for structure-based drug design: expression, refolding and crystallisation.

New techniques in drug discovery are essential for the fast and efficient development of novel innovative drugs to deal with the challenges of the future. Structure determinations of various members of serine proteinases have provided a basis for computer-based drug design within this class of enzymes. In many proteins of interest, however, this course is blocked through a lack of suitable crystals. As a strategy for circumventing such problems, we have investigated the use of surrogate proteins for studying protein-ligand interactions. To test the feasibility of this approach, we have chosen bovine trypsin as a scaffold to reconstruct the ligand binding site of factor Xa. The simple modular design of trypsin, its readiness to crystallise and straightforward handling lends itself to such drug design by proxy. The expression, folding, purification, crystallographic and kinetic characterisation of bovine trypsin forms with factor Xa phenotype are presented.

Animals↗