Computational Insights Into Muscarinic Receptor And Cytochrome P450s With Their Ligands

The modeling of molecular interaction and investigation of pharmacokinetics are two main subjects about computer aided drug design to find drug candidate. In the 1st chapter, some basic methodology and principals of these two areas are introduced. A brief review of ADME prediction, which contained the application of some modern methods, is also included.The human muscarinic M2 receptor belongs to G protein-coupled receptor, and its antagonism is related to treatments of neurodegenerative disease. In the 2nd chapter, both ligand- and structure-based methods were carried out to elucidate the binding mechanism between M2 receptor and its antogonists. The pharmacophore displayed four features, a hydrogen bond acceptor, a positive ionization and two aromatic rings. It was validated by the QSAR model in which R2=0.94 and Q2=0.82. M2 receptor used for docking was built by homology modeling, and optimized by induced-fit docking and molecular dynamics. The docking poses and pharmacophore features had a good match. Our conclusion illustrates the binding mode of M2 antagonists, but the information of selectivity has not been revealed yet.The human cytochrome P450 (CYP) 2A13 and 2A6 share the sequence identity of 94%. However, they exhibit different metabolic activities on carcinogen 4-(Methylnitrosamino)-l-(3-pyridyl)-1-butanone (NNK). Previous experiments reported that CYP2A13 had>300-fold higher in catalytic efficiency (Vmax/Km) than CYP2A6 on NNK. In 3rd chapter, molecular dynamics simulation combined with molecular docking and binding free energy calculation was used to investigate the similarity and dissimilarity in catalytic profiles of the two enzymes on NNK. The results demonstrated that NNK formed a hydrogen bond with Asn297 in both systems, and was stabilized by the hydrophobic residues. NNK mainly interacted with the hydrophobic residues in helix I and the K-02 loop in CYP2A13 while it preferred to contact with the phenylalanine cluster in CYP2A6. Correspondingly, the hydrogen bond acceptor of NNK was the pyridine nitrogen in CYP2A13, but carbonyl oxygen in CYP2A6. The binding free energies calculated by MM-GBSA showed NNK was more stable in CYP2A13 binding site, which were in agreement with the experimental results.