Role of Ligand Reorganization and Conformational Restraints on the Binding Free Energies of DAPY Non-Nucleoside Inhibitors to HIV Reverse Transcriptase

The results of computer simulations of the binding of etravirine (TMC125) and rilpivirine (TMC278) to HIV reverse transcriptase are reported. It is confirmed that consistent binding free energy estimates are obtained with or without the application of torsional restraints when the free energies of imposing the restraints are taken into account. The restraints have a smaller influence on the thermodynamics and apparent kinetics of binding of TMC125 compared to the more flexible TMC278 inhibitor. The concept of the reorganization free energy of binding is useful to understand and categorize these effects. Contrary to expectations, the use of conformational restraints did not consistently enhance convergence of binding free energy estimates due to suppression of binding/unbinding pathways and due to the influence of rotational degrees of freedom not directly controlled by the restraints. Physical insights concerning the thermodynamic driving forces for binding and the role of “jiggling” and “wiggling” motion of the ligands are discussed. Based on these insights we conclude that an ideal inhibitor, if chemically realizable, would possess the electrostatic charge distribution of TMC125, so as to form strong interactions with the receptor, and the larger and more flexible substituents of TMC278, so as to minimize reorganization free energy penalties and the effects of resistance mutations, suitably modified, as in TMC125, so as to disfavor the formation of non-binding competent extended conformations when free in solution.

英格兰社区药房服务及其对中国社会药房发展的启示

目的:探讨英格兰社区药房服务对中国社会药房发展的启示。方法:回顾和探讨2000-2008年英国社区药房各种制度和政策对社区药房服务内容的影响,提出对中国社会药房未来发展的建议。结果与结论:英格兰社区药房的基本服务内容包括配药、重复配药、回收药物、公共健康、提供转诊指导、自我保健以及临床管理。此外,英国皇家药学会也不断推出各项社区药房的额外服务以提高其效能,如抗凝血剂监测服务、特定疾病专用药物管理服务等。这些举措对中国社会药房的发展具有较大启示,也有实际可行性。

黄嘌呤氧化酶抑制剂对环氧合酶的分子对接及药物特性研究

利用计算机辅助药物设计(CADD)技术去探讨403个黄嘌呤氧化酶抑制剂作为治疗痛风药物的潜在可能性。本研究运用Surflex-Dock、FAF-Drugs2、Toxtree的Benigni/Bossa rulebase和PharmMapper对COX-1和COX-2进行柔性分子对接、ADMET预测、致癌性预测和潜在药物靶标预测研究。结果显示化合物ChEMBL 170303和460160有最高的药物潜在价值,可对其进行生物活体及临床研究以了解其确切功效,从而发掘能同时治疗高尿酸血症及炎症的新型抑制剂。