HIV蛋白酶抑制剂的定量构效关系研究及其指导下的修饰

Quantitatives structure-activity relationship and modification of HIV protease inhibitors

HIV蛋白酶是一类用于治疗艾滋病具有潜在价值的关键酶,很多此类酶的抑制剂已经上市.一系列由AHPBA分子的基本骨架进行改造并合成的25个α-羟基β-氨基酸类似物对于HIV蛋白酶具有很高的活性和选择性.我们筛选合适的描述子建立一个二维定量构效关系的模型,模型的均方根误差RMSE=0.09823、相关性系数R=0.97461、F值=30.763、交叉验证的相关系数RCV=0.7071、交叉验证的预测误差平方PRESS=0.588,该模型为HIV蛋白酶抑制剂修饰和设计提供了比较可靠的预测.并且根据“变形钥匙”理论,分别用“杂化肽键”Ψ[CH2NH]、Ψ[CF2NH]、Ψ[COCF2]、替换掉这组类似物中易水解的肽键-CO=NH-,使得这个共轭π键就变成一个较强的单键,变得不易被HIV蛋白酶所水解,从而得到抗AIDS的有效的抑制剂.然后通过原子电荷分布对比、分子对接等方法检验修饰的可能性和合理性.预先设想都在计算结果中得到验证,并且用QSAR模型预测了修饰后分子的活性.

HIV Protease is a key player in curing AIDS. A lot of protease inhibitors have been on the market. The α-hydroxy β-amino acids inhibitors containing AHBA have high activity and significant selectivity. We select some descriptors to built a 2D-quantitatives structure-activity relationship model which yields RMSE = 0.09823, R = 0.97461, F= 30.763, Rcv = 0.7071 and PRESS = 0.588. So we believe that this model is capable of guiding us to design and modify the HIV protease inhibitors. Furthermore, according to the“destroyed key theory”, - CO= NH- were superseded by ψ[CH2NH], ψ[CF2NH] and ψ[COCF2] separately. In this way, we can get some effective inhibitors against AIDS. These assumption are supported by observing the atom electric charge distribution and molecule docking. The QSAR model is used to predict the activities after chemical modification of inhibitors.