Abstract

The drug efflux pump P-glycoprotein (P-gp) has been shown to cause multidrug resistance (MDR) in tumors as well as to influence ADME properties of drug candidates. P-gp is highly promiscuous in its ligand recognition profiles and thus transports numerous structurally and functionally diverse compounds out of tumor cells and accross physiological barriers. Several inhibitors of P-gp mediated drug efflux have been identified in the past two decades, but all of them failed in clinical trials due to severe side effects and lack of efficacy. This further emphasizes the necessity of reliable in-silico tools for prediction of P-gp substrates and inhibitors during the early phases of drug discovery. Therefore, in this thesis, various in silico tools have been utilized to get insights into 3D structural requirements of ligands, their binding modes, as well as their stereoselectivity towards P-gp. Different 2D- and 3D-QSAR models using simple physicochemical and GRID independent molecular descriptors have been constructed across different chemical scaffolds to investigate global structural attributes of P-gp inhibitors. In order to identify most promising P-gp ligands with best potency/lipophilicity or size ratio, we, for the first time, also used ligand efficiency and lipophilic efficiency based approaches. Interestingly, none of the P-gp inhibitors/substrates cross the LipE threshold of 5 for highly promising compounds. This might be linked to the unique entry pathway directly from the membrane bilayer, which is rather unique for transporters and ion channels. Our docking studies provide the first evidence for different binding areas of two diastereomeric compound series and provides evidence for stereoselective ligand recognition of by P-gp. In addition we could show that a benzophenone dimer is well docked in a pose bridging these two distinct binding sites, which further strengthens the hypothesis of multiple, partly overlapping binding sites at P-gp. The work described in this thesis will pave the way for the design of new and more promising inhibitors of P-gp in the future with better ADME properties and reduced toxicity.