基于配体的P糖蛋白底物和抑制剂计算机辅助研究
摘要
P糖蛋白(P-glycoprotein,P-gp)是一类广泛分布于人体的小肠、肝、肾等许多重要器官细胞膜上的跨膜糖蛋白,其生理功能是在ATP酶水解能驱动下将进入细胞的药物(或异物)泵出胞外,降低药物胞内浓度而影响药效。因而,P-gp对药物的吸收、分布和排泄性质有很大影响。此外,由于P-gp在多种癌细胞中也过量表达,常诱导癌细胞产生多药耐药性,而大大降低化疗效果。因此,高效、安全P-gp抑制剂的开发始终是研究开发的热点之一,然而迄今还没有一种P-gp抑制剂药物成功问世。
本文以基于配体的药物设计方法为研究工具,以四类能与P-gp发生特定作用的代表性药物为研究对象,建立了这些药物的结构-活性关系模型,以辅助筛选和设计具有更高活性的P-gp抑制剂药物。主要结果为:
(1)外源性分子:类黄酮。建立了一个类黄酮抑制剂药效团模型,阐明了该类分子作为P-gp抑制剂的必需结构特征。为黄酮和查尔酮两子类分子建立了构效关系模型,确定了影响这两类分子抑制活性的结构基团和物化性质,以指导类黄酮抑制剂药物的进一步合成和筛选。
(2)内源性分子:类固醇。利用三维定量构效关系方法,比较了该类分子分别作为P-gp底物和抑制剂的结构特征。同时,研究和阐明了影响该类分子被动扩散跨膜、被P-gp主动转运、对P-gp有抑制作用三种生物活性的疏水场空间分布,为设计、开发具有更强跨膜能力或更强P-gp抑制活性的类固醇药物提供指导。
(3)抗癌分子:紫杉醇/烷。研究此类分子作为P-gp抑制剂的必需结构特征。所建模型可指导开发新的紫杉烷类P-gp抑制药物。
(4)P-gp和CYP3A4的交叉底物分子。研究者普遍认为P-gp和CYP3A4之间可能采用一种协同作用来共同降低药物生物利用度。因此,本文对这两蛋白的交叉底物进行研究,构建的药效团模型阐明了类固醇类交叉底物和一般交叉底物的必需结构特征,加深了对这两蛋白协同作用机理的理解,为判别可能的P-gp和CYP3A4交叉底物提供指导。
综上,本文通过选择性地研究影响类固醇、类黄酮、紫杉醇/烷及P-gp和CYP3A4交叉底物四类重要分子生物活性的关键结构和物化性质,建立了若干具有良好预测能力的数学模型,有助于为进一步理性筛选、设计、开发P-gp抑制剂药物提供指导,具有重要理论和应用价值。
P-glycoprotein (P-gp) is a transmembrane glycoprotein widely spreaded in many important normal tissues like the intestine, liver and kidney. Its physiological function is to pump a wide variety of drugs and xenobiotics out of the cell under the drive force of ATP hydrolysis energy, resulting in decreased intracellular drug concentration and chemotherapy effect. Thus P-gp greatly influences the absorption, distribution and excretion properties of drugs. In various tumor cells, P-gp is also found to be overexpressed and assumed as the main cause of multi-drug resistance (MDR) of tumor cells and largely decreased chemotherapy effects. Therefore, the development of highly effective and safe P-gp inhibitors is a permanent objective of chemists and pharmacologists. However, up to now there is still no sucessful P-gp inhibitor that has been produced.The object of the present work is to study four selected typical P-gp-related drugs by ligand-based drug design (LBDD) to build certain quantitative structure-activity relationship (QSAR) statistical models and aid the design of novel P-gp inhibitors with potent activity. The main results are as follows:(1) Exogenous molecules: flavonoids. A pharmacophore model clearly identified the critical structural features of flavonoid-based P-gp inhibitors was established. Additionally, certain QSAR models were also obtained for flavone- and chalcone-like flavonoid derivatives indepently, which are useful in aiding the synthesis and screening of new flavonoid inhibitors.(2) Endogenous molecules: steroids. The requisite structural features influencing the biological activites of steroid-based P-gp substrates and inhibitors were identified and compared by 3D-QSAR methods. Meanwhile, the hydrophobic field display in 3D-space of steroids influencing the passive diffusion activity, the active transport activity by P-gp or the inhibitory activity to P-gp of steroids were also studied. All these models provide helpful theoretical aid for new steroid drugs with potent transmembrane activity or inhibitory effects to P-gp.(3) Antitumor molecules: taxanes. The key structural characteristics of series of taxanes as P-gp inhibitors were studied and identified, which are valuable for aiding development of novel taxane-based P-gp inhibitors.(4) Overlapping substrates of P-gp and cytocrome P4503A4 (CYP3A4). These two proteins are assumed to cooperate with each other when decreasing the bioavailability of
drugs. Thus, two pharmacophore models were established, clarifing the structural determinants of general overlapping substrate and steroid-based overlapping substrate of P-gp and CYP3A4 respectively, which are helpful for identifying possible ovelapping interacting drugs of P-gp and CYP3A4.In conclusion, four important P-gp interacting molecules including steroids, flavonoids, taxanes and overlapping substrates of P-gp and CYP3A4 were studied, resulting in dozens of QSAR and pharmacophore models of proper predictability. The models identified the key structural features and chemical/physical properties of the molecules and are valuable and applicable in aiding further development of P-gp inhibitory drugs.
本文以基于配体的药物设计方法为研究工具,以四类能与P-gp发生特定作用的代表性药物为研究对象,建立了这些药物的结构-活性关系模型,以辅助筛选和设计具有更高活性的P-gp抑制剂药物。主要结果为:
(1)外源性分子:类黄酮。建立了一个类黄酮抑制剂药效团模型,阐明了该类分子作为P-gp抑制剂的必需结构特征。为黄酮和查尔酮两子类分子建立了构效关系模型,确定了影响这两类分子抑制活性的结构基团和物化性质,以指导类黄酮抑制剂药物的进一步合成和筛选。
(2)内源性分子:类固醇。利用三维定量构效关系方法,比较了该类分子分别作为P-gp底物和抑制剂的结构特征。同时,研究和阐明了影响该类分子被动扩散跨膜、被P-gp主动转运、对P-gp有抑制作用三种生物活性的疏水场空间分布,为设计、开发具有更强跨膜能力或更强P-gp抑制活性的类固醇药物提供指导。
(3)抗癌分子:紫杉醇/烷。研究此类分子作为P-gp抑制剂的必需结构特征。所建模型可指导开发新的紫杉烷类P-gp抑制药物。
(4)P-gp和CYP3A4的交叉底物分子。研究者普遍认为P-gp和CYP3A4之间可能采用一种协同作用来共同降低药物生物利用度。因此,本文对这两蛋白的交叉底物进行研究,构建的药效团模型阐明了类固醇类交叉底物和一般交叉底物的必需结构特征,加深了对这两蛋白协同作用机理的理解,为判别可能的P-gp和CYP3A4交叉底物提供指导。
综上,本文通过选择性地研究影响类固醇、类黄酮、紫杉醇/烷及P-gp和CYP3A4交叉底物四类重要分子生物活性的关键结构和物化性质,建立了若干具有良好预测能力的数学模型,有助于为进一步理性筛选、设计、开发P-gp抑制剂药物提供指导,具有重要理论和应用价值。
P-glycoprotein (P-gp) is a transmembrane glycoprotein widely spreaded in many important normal tissues like the intestine, liver and kidney. Its physiological function is to pump a wide variety of drugs and xenobiotics out of the cell under the drive force of ATP hydrolysis energy, resulting in decreased intracellular drug concentration and chemotherapy effect. Thus P-gp greatly influences the absorption, distribution and excretion properties of drugs. In various tumor cells, P-gp is also found to be overexpressed and assumed as the main cause of multi-drug resistance (MDR) of tumor cells and largely decreased chemotherapy effects. Therefore, the development of highly effective and safe P-gp inhibitors is a permanent objective of chemists and pharmacologists. However, up to now there is still no sucessful P-gp inhibitor that has been produced.The object of the present work is to study four selected typical P-gp-related drugs by ligand-based drug design (LBDD) to build certain quantitative structure-activity relationship (QSAR) statistical models and aid the design of novel P-gp inhibitors with potent activity. The main results are as follows:(1) Exogenous molecules: flavonoids. A pharmacophore model clearly identified the critical structural features of flavonoid-based P-gp inhibitors was established. Additionally, certain QSAR models were also obtained for flavone- and chalcone-like flavonoid derivatives indepently, which are useful in aiding the synthesis and screening of new flavonoid inhibitors.(2) Endogenous molecules: steroids. The requisite structural features influencing the biological activites of steroid-based P-gp substrates and inhibitors were identified and compared by 3D-QSAR methods. Meanwhile, the hydrophobic field display in 3D-space of steroids influencing the passive diffusion activity, the active transport activity by P-gp or the inhibitory activity to P-gp of steroids were also studied. All these models provide helpful theoretical aid for new steroid drugs with potent transmembrane activity or inhibitory effects to P-gp.(3) Antitumor molecules: taxanes. The key structural characteristics of series of taxanes as P-gp inhibitors were studied and identified, which are valuable for aiding development of novel taxane-based P-gp inhibitors.(4) Overlapping substrates of P-gp and cytocrome P4503A4 (CYP3A4). These two proteins are assumed to cooperate with each other when decreasing the bioavailability of
drugs. Thus, two pharmacophore models were established, clarifing the structural determinants of general overlapping substrate and steroid-based overlapping substrate of P-gp and CYP3A4 respectively, which are helpful for identifying possible ovelapping interacting drugs of P-gp and CYP3A4.In conclusion, four important P-gp interacting molecules including steroids, flavonoids, taxanes and overlapping substrates of P-gp and CYP3A4 were studied, resulting in dozens of QSAR and pharmacophore models of proper predictability. The models identified the key structural features and chemical/physical properties of the molecules and are valuable and applicable in aiding further development of P-gp inhibitory drugs.
引文
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