第二节应用案例2.pdf

计算机辅助药物设计 案例介绍2 1 案例1 Structure-Based Optimization of Novel Azepane Derivatives as PKB Inhibitors J. Med. Chem. 2004, 47, 1375-1390 2 Abstracts 3 4 5 Figure 4. Overlay of X-ray crystal structures of inhibitors 1, 4, 5, and 8 situated in the active site of PKA. The protein backbone ribbon with conformation of side chains relevant for binding interactions with the inhibitors is shown. Conclusion 1.No significant differences in binding affinities for PKA and PKB- αcould be observed. 2.PKA is a suitable surrogate kinase for PKB,and crystal structures of inhibitors cocrystallized with the kinase domain of PKA can be used for molecular modeling studies for a design of active PKB- αinhibitors. 3.Inhibitors 4, 5, and 7 are plasma stable analogues of the original lead 1. 4.Inhibitor4 was used as the new lead structure for further lead optimization of selectivity between PKB and PKA, bioavailability, and tolerability. 案例2 Computer-aided de novo ligand design and docking/molecular dynamics study of Vitamin D receptor agonists 16 Computer-aided de novo ligand design and docking/molecular dynamics study of Vitamin D receptor agonists 1α,25(OH)2D3 exerts a wide variety of biological actions, which is directly mediated by the vitamin D receptor (VDR). However, the treatment with α,25(OH)2D3 is limited because of its side effects. Many analogs and s