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      The Binding Mode of the Sonic Hedgehog Inhibitor Robotnikinin, a Combined Docking and QM/MM MD Study

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          Erroneous activation of the Hedgehog pathway has been linked to a great amount of cancerous diseases and therefore a large number of studies aiming at its inhibition have been carried out. One leverage point for novel therapeutic strategies targeting the proteins involved, is the prevention of complex formation between the extracellular signaling protein Sonic Hedgehog and the transmembrane protein Patched 1. In 2009 robotnikinin, a small molecule capable of binding to and inhibiting the activity of Sonic Hedgehog has been identified, however in the absence of X-ray structures of the Sonic Hedgehog-robotnikinin complex, the binding mode of this inhibitor remains unknown. In order to aid with the identification of novel Sonic Hedgehog inhibitors, the presented investigation elucidates the binding mode of robotnikinin by performing an extensive docking study, including subsequent molecular mechanical as well as quantum mechanical/molecular mechanical molecular dynamics simulations. The attained configurations enabled the identification of a number of key protein-ligand interactions, aiding complex formation and providing stabilizing contributions to the binding of the ligand. The predicted structure of the Sonic Hedgehog-robotnikinin complex is provided via a PDB file as Supplementary Material and can be used for further reference.

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          Most cited references 76

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          Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen

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            VMD: Visual molecular dynamics

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              Comparison of simple potential functions for simulating liquid water


                Author and article information

                Front Chem
                Front Chem
                Front. Chem.
                Frontiers in Chemistry
                Frontiers Media S.A.
                23 October 2017
                : 5
                1Theoretical Chemistry Division, Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck , Innsbruck, Austria
                2Department of Physics, Theoretical Biophysics (T38), Technical University of Munich , Munich, Germany
                3Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck , Innsbruck, Austria
                Author notes

                Edited by: Jean-Philip Piquemal, Sorbonne Universités, France

                Reviewed by: Jitrayut Jitonnom, University of Phayao, Thailand; Albert Poater, University of Girona, Spain

                *Correspondence: Thomas S. Hofer t.hofer@

                This article was submitted to Theoretical and Computational Chemistry, a section of the journal Frontiers in Chemistry

                Copyright © 2017 Hitzenberger, Schuster and Hofer.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Figures: 8, Tables: 3, Equations: 0, References: 78, Pages: 14, Words: 10700
                Original Research


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