FUNCTIONAL-GROUP CONTRIBUTIONS TO DRUG RECEPTOR INTERACTIONS
FUNCTIONAL-GROUP CONTRIBUTIONS TO DRUG RECEPTOR INTERACTIONS
复制标题
DOI：
10.1021/jm00378a021
复制
发表时间：
1984-01-01
影响因子：
7.3
通讯作者：
MARTIN, JL
中科院分区：
文献类型：
--
作者：
ANDREWS, PR;CRAIK, DJ;MARTIN, JL
利用200种药物和酶抑制剂的结合常数和结构组成，计算了10种常见官能团的平均结合能。正如预期的那样，带电基团比极性基团结合得更强，极性基团又比非极性基团结合得更紧。导出的固有结合能（kcal/mol）为（1）带电基团，CO2-，8.2; PO 42-，10.0; N+，11.5;（2）极性基团，N，1.2; OH，2.5; CO，3.4; O或S醚，1.1;卤素，1.3;和（3）非极性基团，C（sp2），0.7; C（sp3），0.8。这些值可用于确定药物与其受体的拟合优度。这是通过将观察到的结合常数与平均结合能进行比较来完成的，所述平均结合能通过将组分基团的固有结合能相加然后减去2个熵相关项（总旋转和平移熵的损失为14 kcal/mol，每个构象自由度为0.7 kcal/mol）来计算。与其受体非常匹配的药物具有显著超过该计算平均值的测量结合能，实例包括地西泮和生物素。如果观察到的结合能比计算的平均值小得多，那么药物显然比平均值更不匹配其受体。这种类型的实例包括甲氨蝶呤和丁丙诺啡。
The binding constants and structural components of 200 drugs and enzyme inhibitors were used to calculate the average binding energies of 10 common functional groups. As expected, charged groups bind more strongly than polar groups, which in turn bind more tightly than nonpolar groups. The derived intrinsic binding energies (in kcal/mol) are (1) charged groups, CO2-, 8.2; PO42-, 10.0; N+, 11.5; (2) polar groups, N, 1.2; OH, 2.5; CO, 3.4; O or S ethers, 1.1; halogens, 1.3; and (3) nonpolar groups, C (sp2), 0.7; C (sp3), 0.8. These values may be used to determine the goodness of fit of a drug to its receptor. This is done by comparing the observed binding constant to the average binding energy calculated by summing the intrinsic binding energies of the component groups and then substracting 2 entropy related terms (14 kcal/mol for the loss of overall rotational and translational entropy and 0.7 kcal/mol for each degree of conformational freedom). Drugs that match their receptors exceptionally well have a measured binding energy that substantially exceeds this calculated average value, examples include diazepam and biotin. If the observed binding energy is very much less than the calculated average value, then the drug apparently matches its receptor less well than average. Examples of this type include methotrexate and buprenorphine.