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Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling

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Abstract

Bacterial β-ketoacyl-acyl carrier protein synthase III (FabH) has become an attractive target for the development of new antibacterial agents which can overcome the increased resistance of these pathogens to antibiotics in clinical use. Despite several efforts have been dedicated to find inhibitors for this enzyme, it is not a straightforward task, mainly due its high flexibility which makes difficult the structure-based design of FabH inhibitors. Here, we present for the first time a Molecular Dynamics (MD) study of the E. colil FabH enzyme to explore its conformational space. We compare the flexibility of this enzyme for the unliganded protein and an enzyme-inhibitor complex and find a correspondence between our modeling results and the experimental evidence previously reported for this enzyme. Furthermore, through a 100 ns MD simulation of the unliganded enzyme we extract useful information related to the concerted motions that take place along the principal components of displacement. We also establish a relation between the presence of water molecules in the oxyanion hole with the conformational stability of structural important loops. Representative conformations of the binding pocket along the whole trajectory of the unliganded protein are selected through cluster analysis and we find that they contain a conformational diversity which is not provided by the X-ray structures of ecFabH. As a proof of this last hypothesis, we use a set of 10 FabH inhibitors and show that they cannot be correctly modeled in any available X-ray structure, while by using our set of conformations extracted from the MD simulations, this task can be accomplish. Finally, we show the ability of short MD simulations for the refinement of the docking binding poses and for MM-PBSA calculations to predict stable protein-inhibitor complexes in this enzyme.

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Acknowledgments

We thank the Vlaams Supercomputer Centrum (VSC) for providing access to the computational resources needed for accomplishing all calculations. Pérez-Castillo Y. thanks the Flemish Interuniversity Council (VLIR) for financial support through the project: “Strengthening research and PhD formation in Computer Sciences and its applications” in the framework of the VLIR-UCLV collaborative program. Cabrera-Pérez M. A. and Pérez-Castillo Y. thank the Spanish Agency of International Cooperation for the Development (AECID) for financial support through the project “Montaje de un laboratorio de química computacional, con fines académicos y científicos, para el diseño racional de nuevos candidatos a fármacos en enfermedades de alto impacto social” (D/024153/09).

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Authors and Affiliations

  1. Laboratory for Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium

    Yunierkis Pérez-Castillo & Matheus Froeyen

  2. Molecular Simulations and Drug Design Department, Centro de Bioactivos Químicos, Universidad Central de Las Villas, Carretera a Camajuaní km 5 ½, Santa Clara, Cuba

    Yunierkis Pérez-Castillo & Miguel Ángel Cabrera-Pérez

  3. Computational Modeling Lab (CoMo), Department of Computer Sciences, Faculty of Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussel, Belgium

    Yunierkis Pérez-Castillo & Ann Nowé

  4. Engineering Department, Pharmacy and Pharmaceutical Technology Area, Faculty of Pharmacy, University Miguel Hernandez, 03550, Alicante, Spain

    Miguel Ángel Cabrera-Pérez

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  1. Yunierkis Pérez-Castillo
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  2. Matheus Froeyen
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  3. Miguel Ángel Cabrera-Pérez
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Correspondence to Yunierkis Pérez-Castillo.

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Pérez-Castillo, Y., Froeyen, M., Cabrera-Pérez, M.Á. et al. Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling. J Comput Aided Mol Des 25, 371–393 (2011). https://doi.org/10.1007/s10822-011-9427-z

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