Accuracy of binding mode prediction with a cascadic stochastic tunneling method

Fischer, Bernhard; Basili, Stefania; Merlitz, H.; Wenzel, Wolfgang

doi:10.1002/prot.21382

Cited by 15 publications

(11 citation statements)

References 64 publications

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“…An optimized docked conformation is shown in Fig. 1f, g. Previous work demonstrated that this approach yields accurate results for binding mode prediction and improves selectivity in library screens for a number of pharmaceutically relevant receptors (Fischer et al 2007;Kokh and Wenzel 2008). …”

Section: Molecular Modelingmentioning

confidence: 91%

hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine

Staudacher

Wang

Wan

et al. 2010

Naunyn-Schmied Arch Pharmacol

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Cardiac side effects of antidepressant drugs are well recognized. Adverse effects precipitated by the tricyclic drug desipramine include prolonged QT intervals, torsade de pointes tachycardia, heart failure, and sudden cardiac death. QT prolongation has been primarily attributed to acute blockade of hERG/I(Kr) currents. This study was designed to provide a more complete picture of cellular effects associated with desipramine. hERG channels were expressed in Xenopus laevis oocytes and human embryonic kidney (HEK 293) cells, and potassium currents were recorded using patch clamp and two-electrode voltage clamp electrophysiology. Ventricular action potentials were recorded from guinea pig cardiomyocytes. Protein trafficking and cell viability were evaluated in HEK 293 cells and in HL-1 mouse cardiomyocytes by immunocytochemistry, Western blot analysis, or colorimetric MTT assay, respectively. We found that desipramine reduced hERG currents by binding to a receptor site inside the channel pore. hERG protein surface expression was reduced after short-term treatment, revealing a previously unrecognized mechanism. When long-term effects were studied, forward trafficking was impaired and hERG currents were decreased. Action potential duration was prolonged upon acute and chronic desipramine exposure. Finally, desipramine triggered apoptosis in cells expressing hERG channels. Desipramine exerts at least four different cellular effects: (1) direct hERG channel block, (2) acute reduction of hERG surface expression, (3) chronic disruption of hERG trafficking, and (4) induction of apoptosis. These data highlight the complexity of hERG-associated drug effects.

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Section: Molecular Modelingmentioning

confidence: 91%

hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine

Staudacher

Wang

Wan

et al. 2010

Naunyn-Schmied Arch Pharmacol

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“…Further information on the docking method and its applications of docking performance for several systems has been reported elsewhere. [53, 66–68] For all parameters not explicitly stated, default values were used.…”

Section: Methodsmentioning

confidence: 99%

Modeling loop backbone flexibility in receptor‐ligand docking simulations

Tristram

Wenzel

2012

J Comput Chem

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The relevance of receptor conformational change during ligand binding is well documented for many pharmaceutically relevant receptors, but is still not fully accounted for in in silico docking methods. While there has been significant progress in treatment of receptor side chain flexibility sampling of backbone flexibility remains challenging because the conformational space expands dramatically and the scoring function must balance protein-protein and protein-ligand contributions. Here, we investigate an efficient multistage backbone reconstruction algorithm for large loop regions in the receptor and demonstrate that treatment of backbone receptor flexibility significantly improves binding mode prediction starting from apo structures and in cross docking simulations. For three different kinase receptors in which large flexible loops reconstruct upon ligand binding, we demonstrate that treatment of backbone flexibility results in accurate models of the complexes in simulations starting from the apo structure. At the example of the DFG-motif in the p38 kinase, we also show how loop reconstruction can be used to model allosteric binding. Our approach thus paves the way to treat the complex process of receptor reconstruction upon ligand binding in docking simulations and may help to design new ligands with high specificity by exploitation of allosteric mechanisms.

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“…Ligands are docked using a cascaded version (Fischer et al, 2007) of a stochastic tunneling algorithm (Merlitz et al, 2003) which samples translations of the center-of-mass and rotations of the ligand, as well as intra-molecular conformational changes. In addition to the degrees of freedom of the ligand, receptor conformational change is accounted for in selected side chains.…”

Section: Docking With Flexscreenmentioning

confidence: 99%