Biomedical subjects

Matthias Rarey

Publications and source records attributed to Matthias Rarey.

8 recordsLinked to original sources

PubMed2006

Molecular complexes at a glance: automated generation of two-dimensional complex diagrams.

MOTIVATION: In this paper a new algorithmic approach is presented, which automatically generates structure diagrams of molecular complexes. A complex diagram contains the ligand, the amino acids of the protein interacting with the ligand and the hydrophilic interactions schematized as dashed lines between the corresponding atoms. The algorithm is based on a combinatorial optimization strategy which solves parts of the layout problem non-heuristically. The depicted molecules are represented as structure diagrams according to the chemical nomenclature. Due to the frequent usage of complex diagrams in the scientific literature as well as in text books dealing with structural biology, biochemistry and medicinal chemistry, the new algorithm is a key element for computer applications in these areas. RESULTS: The method was implemented in the new software tool PoseView. It was tested on a representative dataset containing 305 protein-ligand complexes in total from the Brookhaven Protein Data Bank. PoseView was able to find collision-free layouts for more than three quarters of all complexes. In the following the layout generation algorithm is presented and, additional to the statistical results, representative test cases demonstrating the challenges of the layout generation will be discussed. AVAILABILITY: The method is available as a webservice at http://www.zbh.uni-hamburg.de/poseview.

Algorithms↗

PubMed2006

FlexNovo: structure-based searching in large fragment spaces.

We present a new molecular design program, FlexNovo, for structure-based searching within large fragment spaces following a sequential growth strategy. The fragment spaces consist of several thousands of chemical fragments and a corresponding set of rules that specify how the fragments can be connected. FlexNovo is based on the FlexX molecular docking software and makes use of its incremental construction algorithm and the underlying chemical models. Interaction energies are calculated by using standard scoring functions. Several placement geometry, physicochemical property (drug-likeness), and diversity filter criteria are directly integrated into the "build-up" process. FlexNovo has been used to design potential inhibitors for four targets of pharmaceutical interest (dihydrofolate reductase, cyclin-dependant kinase 2, cyclooxygenase-2, and the estrogen receptor). We have carried out calculations using different diversity parameters for each of these targets and generated solution sets containing up to 50 molecules. The compounds obtained show that FlexNovo is able to generate a diverse set of reasonable molecules with drug-like properties. The results, including an automated similarity analysis with the Feature Tree program, indicate that FlexNovo often reproduces structural motifs as well as the corresponding binding modes seen in known active structures.

Cyclin-Dependent Kinase 2↗

PubMed2005

Multiple-ligand-based virtual screening: methods and applications of the MTree approach.

We present a novel approach for ligand-based virtual screening by combining query molecules into a multiple feature tree model called MTree. All molecules are described by the established feature tree descriptor, which is derived from a topological molecular graph. A new pairwise alignment algorithm leads to a consistent topological molecular alignment based on chemically reasonable matching of corresponding functional groups. These multiple feature tree models find application in ligand-based virtual screening to identify new lead structures for chemical optimization. Retrospective virtual screening with MTree models generated for angiotensin-converting enzyme and the alpha1a receptor on a large candidate database yielded enrichment factors up to 71 for the first 1% of the screened database. MTree models outperformed database searches using single feature trees in terms of hit rates and quality and additionally identified alternative molecular scaffolds not included in any of the query molecules. Furthermore, relevant molecular features, which are known to be important for affinity to the target, are identified by this new methodology.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2004

FlexX-Scan: fast, structure-based virtual screening.

We present a new software module, FlexX-Scan, for high-throughput, structure-based virtual screening. FlexX-Scan was developed with the aim to further speed up the virtual screening process. Based on the incremental construction docking tool FlexX (Rarey et al., J Mol Biol 1996;261:470-489), a compact descriptor for representing favorable protein interaction spots within the protein binding site has been developed. The descriptor is calculated using special-purpose clustering techniques applied to the usual interaction points created by FlexX. The algorithm automatically detects a small set of interaction spots in the binding site for positioning ligand functional groups. The parametrizations of the base placement and incremental construction algorithms have been adapted to the new interaction model. We tested the software tool on a diverse set of 200 protein-ligand complexes from the protein database (PDB) (Kramer et al., Proteins 1999;37:228-241). On average, the algorithm proposes about 90 interaction spots per binding site compared to about 1000 interaction dots in FlexX. We observe that the docking solutions of FlexX-Scan have a root-mean-square deviation from the crystal structure similar to the deviation of docking solutions of standard FlexX. For further validation we also performed virtual screening experiments for cyclin-dependent kinase 2, thrombin, angiotensin-converting enzyme, and dihydrofolat reductase. In these experiments, we screened a set of 34,000 random compounds and a number of known actives for each target. With FlexX-Scan, we achieved comparable enrichments to standard FlexX, with an averaged computing time of 5-10 s per compound, depending on parametrization.

Algorithms↗

PubMed2004

Novel technologies for virtual screening.

There are several methods for virtual screening of databases of small organic compounds to find tight binders to a given protein target. Recent reviews in Drug Discovery Today have concentrated on screening by docking and by pharmacophore searching. Here, we complement these reviews by focusing on virtual screening methods that are based on analyzing ligand similarity on a structural level. Specifically, we concentrate on methods that exploit structural properties of the complete ligand molecules, as opposed to using just partial structural templates, such as pharmacophores. The in silico procedure of virtual screening (VS) and its relationship to the experimental procedure, HTS, is discussed, new developments in the field are summarized and perspectives on future research are offered.

Combinatorial Chemistry Techniques↗

PubMed2002

Flexible docking under pharmacophore type constraints.

FLEXX-PHARM, an extended version of the flexible docking tool FLEXX, allows the incorporation of information about important characteristics of protein-ligand binding modes into a docking calculation. This information is introduced as a simple set of constraints derived from receptor-based type pharmacophore features. The constraints are determined by selected FLEXX interactions and inclusion volumes in the receptor active site. They guide the docking process to produce a set of docking solutions with particular properties. By applying a series of look-ahead checks during the flexible construction of ligand fragments within the active site, FLEXX-PHARM determines which partially built docking solutions can potentially obey the constraints. Solutions that will not obey the constraints are deleted as early as possible, often decreasing the calculation time and enabling new docking solutions to emerge. FLEXX-PHARM was evaluated on various individual protein-ligand complexes where the top docking solutions generated by FLEXX had high root mean square deviations (RMSD) from the experimentally observed binding modes. FLEXX-PHARM showed an improvement in the RMSD of the top solutions in most cases, along with a reduction in run time. We also tested FLEXX-PHARM as a database screening tool on a small dataset of molecules for three target proteins. In two cases, FLEXX-PHARM missed one or two of the active molecules due to the constraints selected. However, in general FLEXX-PHARM maintained or improved the enrichment shown with FLEXX, while completing the screen in considerably less run time.

Algorithms↗

PubMedDate not supplied

Automated drawing of structural molecular formulas under constraints.

In this paper, we present a new algorithm for automated drawing of 2D structural formulas of molecules. The algorithm is based on the classical scheme of a drawing queue placing the molecular fragments in a sequential way. We extend the concept of so-called prefabricated units developed for complex ring systems to automatically created drawing units for chains and rings which will then be assembled in a sequential fashion. The approach is fast and can be naturally extended to the problem of drawing molecules with common core structures. Further on, we present an algorithm that allows the drawing of 2D structural formulas under directional constraints assigned to a subset of bonds. Since no numerical optimization is necessary, the algorithm creates drawings of small organic molecules on the order of 500 structures per second. The new algorithm is relevant for all kinds of prediction and analysis software presenting a large number of probably similar molecular structures to the user of the software.

Journal Article↗

PubMedDate not supplied

Fully automated flexible docking of ligands into flexible synthetic receptors using forward and inverse docking strategies.

The prediction of the structure of host-guest complexes is one of the most challenging problems in supramolecular chemistry. Usual procedures for docking of ligands into receptors do not take full conformational freedom of the host molecule into account. We describe and apply a new docking approach which performs a conformational sampling of the host and then sequentially docks the ligand into all receptor conformers using the incremental construction technique of the FlexX software platform. The applicability of this approach is validated on a set of host-guest complexes with known crystal structure. Moreover, we demonstrate that due to the interchangeability of the roles of host and guest, the docking process can be inverted. In this inverse docking mode, the receptor molecule is docked around its ligand. For all investigated test cases, the predicted structures are in good agreement with the experiment for both normal (forward) and inverse docking. Since the ligand is often smaller than the receptor and, thus, its conformational space is more restricted, the inverse docking approach leads in most cases to considerable speed-up. By having the choice between two alternative docking directions, the application range of the method is significantly extended. Finally, an important result of this study is the suitability of the simple energy function used here for structure prediction of complexes in organic media.

Algorithms↗