Abstract：
DNA gyrase and topoisomerase IV play significant role in maintaining the correct structure of DNA during replication and they have been identified as validated targets in antibacterial drug discovery. Inadequate pharmacokinetic properties are responsible for many failures during drug discovery and their estimation in the early phase of this process maximizes the chance of getting useful drug candidates. Passive gastrointestinal absorption of a selected group of thirteen dual DNA gyrase and topoisomerase IV inhibitors was estimated using two in vitro tests - parallel artificial membrane permeability assay (PAMPA) and biopartitioning micellar chromatography (BMC). Due to good correlation between obtained results, passive gastrointestinal absorption of remaining ten compounds was estimated using only BMC. With this experimental setup, it was possible to identify compounds with high values of retention factors (k) and highest expected passive gastrointestinal absorption, and compounds with low values of k for which low passive gastrointestinal absorption is predicted. Quantitative structure-retention relationship (QSRR) modelling was performed by creating multiple linear regression (MLR), partial least squares (PLS) and support vector machines (SVM) models. Descriptors with the highest influence on retention factor were identified and their interpretation can be used for the design of new compounds with improved passive gastrointestinal absorption.
摘要：
DNA促旋酶和拓扑异构酶IV在复制过程中保持DNA的正确结构中起着重要作用，并且它们已被鉴定为抗菌药物发现中的有效靶标。药物动力学特性不足是药物发现过程中许多失败的原因，并且在该过程的早期阶段对其进行估计会使获得有用候选药物的机会最大化。使用两个体外测试-平行人工膜通透性测定（PAMPA）和生物颗粒胶束色谱（BMC）估计了选定的13种双DNA促旋酶和拓扑异构酶IV抑制剂的被动胃肠道吸收。由于获得的结果之间具有良好的相关性，仅使用BMC估计其余10种化合物的被动胃肠道吸收。有了这个实验装置，这是可能的，以确定化合物的保留因子（K）和最高预期的被动胃肠道吸收的高值，和具有低k值的化合物，预测其被动胃肠道吸收低。通过创建多元线性回归(MLR)进行定量结构保留关系(QSRR)建模，偏最小二乘(PLS)和支持向量机(SVM)模型。鉴定了对保留因子影响最大的描述符，它们的解释可用于设计具有改善的被动胃肠道吸收的新化合物。
