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Tomberg A.,McGill University | Pottel J.,McGill University | Liu Z.,McGill University | Labute P.,Chemical Computing Group Inc. | Moitessier N.,McGill University
Angewandte Chemie - International Edition | Year: 2015

Adverse drug reactions are commonly the result of cytochrome P450 enzymes (CYPs) converting the drugs into reactive metabolites. Thus, information about the CYP bioactivation of drugs would not only provide insight into metabolic stability, but also into the potential toxicity. For example, oxidation of phenyl rings may lead to either toxic epoxides or safer phenols. Herein, we demonstrate that the potential to form reactive metabolites is encoded primarily in the properties of the molecule to be oxidized. While the enzyme positions the molecule inside the binding pocket (selects the site of metabolism), the subsequent reaction is only dependent on the substrate itself. To test this hypothesis, we used this observation as a predictor of drug inherent toxicity. This approach was used to successfully identify the formation of reactive metabolites in over 100 drug molecules. These results provide a new perspective on the impact of functional groups on aromatic oxidation of drugs and their effects on toxicity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Clark A.M.,Chemical Computing Group Inc.
Journal of Chemical Information and Modeling | Year: 2010

Drug discovery projects often involve organizing compounds in the form of a hierarchical tree, where each node is a substructure fragment shared by all of its descendent nodes. A method is described for producing 2D depiction layout coordinates for each of the nodes in such a tree, ensuring that common fragments within molecular structures are drawn in an identical way, and arranged with a consistent orientation. This is achieved by first deriving a common numbering scheme for common fragments, then using this scheme to redepict each of the molecules, one fragment at a time, so that common fragments have common depiction motifs. Once complete, the distinct root branches can be overlaid onto each other, after which all of the fragments and whole molecules have a common layout and orientation. Several methods are described for preparing visual representations of molecular structure hierarchies alongside activity information. Combining high level tree display and structure depiction showing common features readily facilitates insight into structure-activity relationships. © 2010 American Chemical Society. Source

Labute P.,Chemical Computing Group Inc.
Journal of Chemical Information and Modeling | Year: 2010

We present a method for conformational search of complex molecular systems such as macrocycles and protein loops. The method is based on perturbing an existing conformation along a molecular dynamics trajectory using initial atomic velocities with kinetic energy concentrated on the low-frequency vibrational modes, followed by energy minimization. A novel Chebyshev polynomial filter is used to heavily dampen the high-frequency components of a randomly generated Maxwell-Boltzmann velocity vector. The method is very efficient, even for large systems; it is straightforward to implement and requires only standard force-field energy and gradient evaluations. The results of several computational experiments suggest that the method is capable of efficiently sampling low-strain energy conformations of complex systems with nontrivial nonbonded interaction networks. © 2010 American Chemical Society. Source

Chemical Computing Group Inc. | Date: 2009-09-29

Software used for protein structure research and analysis in the pharmaceutical, biotechnological, chemical and food industry.

Korb O.,University of Konstanz | Korb O.,Cambridge Crystallographic Data Center | Ten Brink T.,University of Konstanz | Raj F.R.D.V.P.,University of Konstanz | And 2 more authors.
Journal of Computer-Aided Molecular Design | Year: 2012

Due to the large number of different docking programs and scoring functions available, researchers are faced with the problem of selecting the most suitable one when starting a structure-based drug discovery project. To guide the decision process, several studies comparing different docking and scoring approaches have been published. In the context of comparing scoring function performance, it is common practice to use a predefined, computer-generated set of ligand poses (decoys) and to reevaluate their score using the set of scoring functions to be compared. But are predefined decoy sets able to unambiguously evaluate and rank different scoring functions with respect to pose prediction performance? This question arose when the pose prediction performance of our piecewise linear potential derived scoring functions (Korb et al. in J Chem Inf Model 49:84-96, 2009) was assessed on a standard decoy set (Cheng et al. in J Chem Inf Model 49:1079-1093, 2009). While they showed excellent pose identification performance when they were used for rescoring of the predefined decoy conformations, a pronounced degradation in performance could be observed when they were directly applied in docking calculations using the same test set. This implies that on a discrete set of ligand poses only the rescoring performance can be evaluated. For comparing the pose prediction performance in a more rigorous manner, the search space of each scoring function has to be sampled extensively as done in the docking calculations performed here. We were able to identify relative strengths and weaknesses of three scoring functions (ChemPLP, GoldScore, and Astex Statistical Potential) by analyzing the performance for subsets of the complexes grouped by different properties of the active site. However, reasons for the overall poor performance of all three functions on this test set compared to other test sets of similar size could not be identified. © Springer Science+Business Media B.V. 2012. Source

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