Chellappan Sripriya, Kairys Visvaldas, Fernandes Miguel X, Schiffer Celia, Gilson Michael K
Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850, USA.
Proteins. 2007 Aug 1;68(2):561-7. doi: 10.1002/prot.21431.
Crystallographic data show that various substrates of HIV protease occupy a remarkably uniform region within the binding site; this region has been termed the substrate envelope. It has been suggested that an inhibitor that fits within the substrate envelope should tend to evade viral resistance because a protease mutation that reduces the affinity of the inhibitor will also tend to reduce the affinity of substrate, and will hence decrease the activity of the enzyme. Accordingly, inhibitors that fit the substrate envelope better should be less susceptible to clinically observed resistant mutations, since these must also allow substrates to bind. The present study describes a quantitative measure of the volume of a bound inhibitor falling outside the substrate envelope, and observes that this quantity correlates with the inhibitor's losses in affinity to clinically relevant mutants. This measure may thus be useful as a penalty function in the design of robust HIV protease inhibitors.
晶体学数据表明，HIV蛋白酶的各种底物在结合位点内占据一个非常一致的区域；该区域被称为底物包膜。有人提出，适合底物包膜的抑制剂应倾向于避免病毒耐药性，因为降低抑制剂亲和力的蛋白酶突变也往往会降低底物的亲和力，从而降低酶的活性。因此，更适合底物包膜的抑制剂应该对临床观察到的耐药突变不太敏感，因为这些突变也必须允许底物结合。本研究描述了一种对结合在底物包膜外的抑制剂体积的定量测量，并观察到该量与抑制剂对临床相关突变体的亲和力损失相关。因此，这种测量方法在设计强效HIV蛋白酶抑制剂时作为惩罚函数可能是有用的。
