喹诺酮药物的定量结构-活性关系

Quantitative structure-activity relationship study for quinolones.

喹诺酮类抗菌素是一类重要的抗菌药物.本文对32个喹诺酮类分子进行了HF/6-31G*水平的结构优化,在优化结构上获得了分子的表面静电势分布,并在此基础上对其统计导出的参数进行了计算,同时计算了反映三维信息的3D-Morse参数,其后,运用多元线性回归方法对喹诺酮分子抑制金黄色葡萄球菌DNA促旋酶(QR-gy-rase)活性、人类Ⅱ型拓扑异构酶(TOPO-Ⅱ)的抑制活性、以及二者抑制活性之差与分子的结构参数进行了关联.结果表明:分子静电势参数结合三维3D-Morse参数可以很好地用于喹诺酮类化合物抑制DNA促旋酶、TOPO-Ⅱ活性与分子结构间的定量关系,并能有效地区分抑制两种酶的活性;同时结合3D-Morse参数的静电势参数被成功应用到定量结构-活性关系研究中.

The quinolone is an important kind of antibacterial agents. Ab initio calculations were performed for all 32 quinolones at the HF/6-31G＊ level. Electrostatic potentials and subsequently derived statistically-based structural descriptors, the 3D-Morse descriptors were obtained. Linear relationships between the inhibition of OR-gyrase, TOPO- Ⅱ and theoretical descriptors were established by multiple regression method. It appeared that the quantities derived from electrostatic potentials, together with the 3D-Morse descriptors can be well used to express the quanti- tative structure-activity relationships of quinolones. And the models could identify how the structure of the molecules in question could be modified to produce good inhibition of gyrase and simultaneously reduce inhibition of TO- PO-Ⅱ. Moreover, the electrostatic potentials parameter together with 3D-Morse descriptors were successful applied in the QSAR study.