Ligand-Based Computer-Aided Drug Design Of P-Glycoprotein Substrates And Inhibitors

P-glycoprotein (P-gp) is a transmembrane glycoprotein widely spreaded in many important normal tissues like the intestine, liver and kidney. Its physiological function is to pump a wide variety of drugs and xenobiotics out of the cell under the drive force of ATP hydrolysis energy, resulting in decreased intracellular drug concentration and chemotherapy effect. Thus P-gp greatly influences the absorption, distribution and excretion properties of drugs. In various tumor cells, P-gp is also found to be overexpressed and assumed as the main cause of multi-drug resistance (MDR) of tumor cells and largely decreased chemotherapy effects. Therefore, the development of highly effective and safe P-gp inhibitors is a permanent objective of chemists and pharmacologists. However, up to now there is still no sucessful P-gp inhibitor that has been produced.The object of the present work is to study four selected typical P-gp-related drugs by ligand-based drug design (LBDD) to build certain quantitative structure-activity relationship (QSAR) statistical models and aid the design of novel P-gp inhibitors with potent activity. The main results are as follows:(1) Exogenous molecules: flavonoids. A pharmacophore model clearly identified the critical structural features of flavonoid-based P-gp inhibitors was established. Additionally, certain QSAR models were also obtained for flavone- and chalcone-like flavonoid derivatives indepently, which are useful in aiding the synthesis and screening of new flavonoid inhibitors.(2) Endogenous molecules: steroids. The requisite structural features influencing the biological activites of steroid-based P-gp substrates and inhibitors were identified and compared by 3D-QSAR methods. Meanwhile, the hydrophobic field display in 3D-space of steroids influencing the passive diffusion activity, the active transport activity by P-gp or the inhibitory activity to P-gp of steroids were also studied. All these models provide helpful theoretical aid for new steroid drugs with potent transmembrane activity or inhibitory effects to P-gp.(3) Antitumor molecules: taxanes. The key structural characteristics of series of taxanes as P-gp inhibitors were studied and identified, which are valuable for aiding development of novel taxane-based P-gp inhibitors.(4) Overlapping substrates of P-gp and cytocrome P4503A4 (CYP3A4). These two proteins are assumed to cooperate with each other when decreasing the bioavailability ofdrugs. Thus, two pharmacophore models were established, clarifing the structural determinants of general overlapping substrate and steroid-based overlapping substrate of P-gp and CYP3A4 respectively, which are helpful for identifying possible ovelapping interacting drugs of P-gp and CYP3A4.In conclusion, four important P-gp interacting molecules including steroids, flavonoids, taxanes and overlapping substrates of P-gp and CYP3A4 were studied, resulting in dozens of QSAR and pharmacophore models of proper predictability. The models identified the key structural features and chemical/physical properties of the molecules and are valuable and applicable in aiding further development of P-gp inhibitory drugs.