molecules-20-08316-v2.pdf

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Molecules 2015 , 20 , 8316-8340; doi:10.3390/molecules20058316 molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Structure Based Modeling of Small Molecules Binding to the TLR7 by Atomistic Level Simulations Francesco Gentile 1 , Marco A. Deriu 2,† , Ginevra Licandro 2,† , Alessio Prunotto 2 , Andrea Danani 2 and Jack A. Tuszynski 1,3, * 1 Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada; E-Mail: [email protected] 2 Institute of Computer Integrated Manufacturing for Sustainable Innovation, Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland (SUPSI), Manno CH-6928, Switzerland; E-Mails: [email protected] (M.A.D.); [email protected] (G.L.); [email protected] (A.P.); [email protected] (A.D.) 3 Cross Cancer Institute, Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-780-964-4517. Academic Editor: D. Hadjipavlou-Litina Received: 29 March 2015 / Accepted: 30 April 2015 / Published: 8 May 2015 Abstract: Toll-Like Receptors (TLR) are a large family of proteins involved in the immune system response. Both the activation and the inhibition of these receptors can have positive effects on several diseases, including viral pathologies and cancer, therefore prompting the development of new compounds. In order to provide new indications for the design of Toll-Like Receptor 7 (TLR7)-targeting drugs, the mechanism of interaction between the TLR7 and two important classes of agonists (imidazoquinoline and adenine derivatives) was investigated through docking and Molecular Dynamics simulations. To perform the computational analysis, a new model for the dimeric form of the receptors was necessary and therefore created. Qualitative and quantitative differences between agonists and inactive compounds were determined. The in silico results were compared with previous experimental observations and employed to define the ligand binding mechanism of TLR7. OPEN ACCESS
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Molecules 2015 , 20 8317 Keywords: toll-like receptors; molecular docking; homology modeling; molecular dynamics; imidazoquinoline; immune system; adenine derivatives 1. Introduction The human immune system has been traditionally divided into the innate immune system and the adaptive immune system. The innate immune system’s main function is to recognize pathogen-associated molecular patterns (PAMPs) [1]. This process allows the immune system to distinguish self from non-self. The PAMPs recognized by the innate immune system are fixed in the genome, whereas in the adaptive immune system new receptors are acquired following antigen exposure. In a healthy person the innate and adaptive immune systems work together and mount a defensive response to infection.
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