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

Promotores: A.P. IJzerman, H.W.T. van Vlijmen

Bart Lenselink
07 juni 2017
Thesis in Leiden Repository

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.