Application Of CADD To Explore QSAR Of Andrographolide Derivatives As α-glucosidase Inhibitors And Establish The Prediction System Of Their Transmembrane Transport

Andrographolide is the main active ingredient of Andrographis paniculate. It has been reported that andrographolide has broad pharmacological activities, such as an anti-bacterial, anti-malarial, anti-inflammatory, anti-tumor, immunological regulation and hepatoprotective effects. Further researches about andrographolide reveal more application of this compound. Recent studies exhibited that andrographolide could reduce blood glucose of diabetes rats and andrographolide derivatives might decrease blood glucose level by inhibiting a-glucosidase after meal. Such pharmacological activity of inhibiting a-glucosidase would greatly contribute to the treatment for diabetes. So far, however, there has been little andrographolide derivative coming into the market as a-glucosidase inhibitor at present, while lots of researches have modified the structures of andrographolide derivatives to develop more potent inhibitors of a-glucosidase.In this background, more and more andrographolide derivatives with inhibitory activity to a-glucosidase have been synthesized. These preceding works will promote the development of a-glucosidase inhibitors. Nevertheless, the traditional procedure to develop drug would to some extent block the development of andrographolide derivatives due to long research circle, high-cost and poor pharmacokinetics characters.Along with the development of computer technique and extension of pharmaceutical databases, computer aided drug design (CADD) has earned re-interesting because of high efficiency, low-cost and extensive application. CADD is frequently utilized to assist the development of drug and there have been lots of drugs designed by CADD in the market. In this context, CADD would significantly contribute to the development of andrographolide derivatives as a-glucosidase inhibitors.Objective:QSAR information will greatly promote the development of andrographolide derivatives, but there is not enough data about this at present. Hence, this research would build the 2D and 3D-QSAR model of andrographolide derivatives as a-glucosidase inhibitors. These models could be utilized to investigate the important fragments and distribution of different force fields which are closely related to the inhibitory activity. Moreover, the potential active sites and key residues were obtained by homology modeling and docking. Information about the active sites and key residues should greatly contribute to the discovery of new a-glucosidase inhibitors.Pharmacokinetic characteristics of candidates, especially the action of crossing human intestinal membrane and blood brain barrier, are the necessary aspect for developing new drug. In the light of the close relationship between compounds' structure and their pharmacokinetic characters, this research built the human intestinal absorption (HIA) prediction system and blood brain barrier (BBB) prediction system to predict the pharmacokinetic features of andrographolide derivatives by using CADD and specific cells'model.Method:1 QSAR studies on andrographolide derivatives as a-glucosidase inhibitors(1) HQSAR was used to build the 2D-QSAR of andrographolide derivatives as a-glucosidase inhibitors and 3D-QSAR models were constructed by both CoMFA and CoMSIA methods. The best QSAR model was used to predict the inhibitory activity of Al-1 which was a new andrographolide derivative.(2) Lineweaver-Burk method was utilized to judge the enzyme reaction style of andrographolide derivatives inhibiting a-glucosidase. And then, the potential active sites and key residues were explored by homology modeling and docking method.2 The establishment of systems to predict andrographolide derivatives' action of crossing human intestinal membrane and blood brain barrier.(1) Volsurf was employed to construct virtual HIA model, which was applied to predict the HIA values of andrographolide derivatives.(2) Volsurf was used to establish virtual BBB model, which was applied to predict the andrographolide derivatives' possibillities to across the BBB.Results:1 QSAR studies on andrographolide derivatives as a-glucosidase inhibitors(1) The 2D-QSAR model was successfully built and the result was supported by cross-validation coefficient (0.730), correlation coefficient (0.945), standard error (0.104) and slope (1.01); the best 3D-QSAR model was validated by cross-validation coefficient (0.794), correlation coefficient (0.941), slope (0.933) and standard error (0.104).(2) The homology model of a-glucosidase was validated by RMSD (1.745 A) of structural alignment. The predicted strong inhibitors'ARs of the two potential active sites were 88.9% and 77.8% respectively.2 The establishment of systems to predict andrographolide derivatives' action of crossing human intestinal membrane and blood brain barrier.(1) The virtual HIA model was verified by cross-validation coefficient (0.72), correlation coefficient (0.932) and slope (0.938).(2) The virtual BBB model was confirmed by cross-validation coefficient (0.64), accuracy rate of test set (78%).Conclusion:(1) The 2D-QSAR model exhibited the important fragments of andrographolide derivatives, which were closely related to bio-activity; the 3D-QSAR model could exhibit the distribution of different force fields, which is closely related to bio-activity. Combining 2D and 3D-QSAR model, the information from QSAR models would be more comprehensive and precise.(2) The homology model ofα-glucosidase could be used to explore the potential active sites and key residues. And the two potential active sites had great recognition to andrographolide derivatives with strong inhibitory activities toα-glucosidase.(3) The virtual HIA model would contribute to the prediction of the pharmacokinetic characteristics of andrographolide derivatives asα-glucosidase inhibitors.(4) The virtual BBB model would contribute to the prediction of the pharmacokinetic characteristics of andrographolide derivatives as a-glucosidase inhibitors.