Clavis Aurea? Structure-enabled approaches of identifying and optimizing GPCR ligands

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Clavis Aurea? Structure-enabled approaches of identifying and optimizing GPCR ligands

Type: Doctoral Thesis
Title: Clavis Aurea? Structure-enabled approaches of identifying and optimizing GPCR ligands
Author: Lenselink, E.B.
Issue Date: 2017-06-07
Keywords: Computer Aided Drug Design,
G Protein-Coupled Receptors
Abstract: The center piece of this thesis is the key-lock metaphor, specifically in the context of computer-aided drug design. This concept was introduced in chapter 1 where the process of drug discovery and lead optimization is discussed. Due to the fact that there are many locks (proteins) and even more keys (ligands), computational research can provide an interesting opportunity to aid and speedup drug discovery. Different methods are introduced in chapter 1, which were used throughout this thesis. In chapter 2 an overview is provided of the different methods of docking and Virtual Screening in the context of GPCRs. Chapter 3 demonstrates the importance of including water molecules in Virtual Screening. In Chapter 4 a Virtual Screen is applied with explicit water molecules on the Adenosine A2A receptor. Chapter 5 presents and discusses an alternative method of analyzing Virtual Screens, Interaction Fingerprints. In Chapter 6 it is demonstrated that more recent statistical methods like deep neural networks are able to outperform other methods, like naïve bayes and random forests. Chapter 7 introduces a method of calculating relative binding energy differences, Free Energy Perturbation (FEP). In Chapter 8 we conclude the thesis with general conclusions and an outlook of the field.
Promotor: Supervisor: A.P. IJzerman, H.W.T. van Vlijmen
Faculty: Science
University: Leiden
Uri: urn:isbn:9789462956711
Handle: http://hdl.handle.net/1887/49402
 

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application/pdf Chapter 8 829.1Kb View/Open
application/pdf Curriculum Vitae 144.4Kb View/Open
application/pdf Summary in English 151.8Kb View/Open
application/pdf Summary in Dutch 151.0Kb View/Open
application/pdf Publications_Acknowledgements 160.7Kb View/Open
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