摘要
运用密度泛函理论(DFT)和线性回归分析等方法研究了黄酮类化合物抑制MMP-9的定量结构-活性关系(QSAR)和结构修饰.研究发现,黄酮类化合物抑制MMP-9的实验生物活性数据-lg EC50值与计算获得的黄酮类化合物的最低空分子轨道能量及分子水合能之间均存在着良好的线性关系;留一法交叉验证结果表明,所建立的两个相应的QSAR模型都具有良好的稳定性和预测能力.进一步研究发现,在黄酮类化合物分子的A环、B环和C环上的合适部位选用供电子能力较强、能降低分子水合能的取代基团对其进行结构修饰,有利于提高修饰后的分子抑制MMP-9的生物活性.根据对木犀草素(Luteolin)分子进行结构修饰的结果(共33种化合物),我们提出了黄酮类化合物抑制MMP-9可能的作用机理,并设计出8种经结构修饰后生物活性有显著提高的MMP-9抑制剂,希望将来得到实验的证实.
Density functional theory （DFT） and linear regression analysis method are used to investigate the quantitative structure-activity relationship （QSAR） and structural modification for the inhibition of MMP-9 by flavonoids. It is found that there are good linear relationships between the experimental biological activity data （-1g EC50） for the inhibition of MMP-9 by flavonoids and the calculated lowest unoccupied molecular orbital energies and the molecular hydration energies of flavonoids. The results from leave-one-out cross-validation show that the established two QSAR models have good stability and prediction ability. Further studies indicate that the biological activities for the modified molecules on MMP-9 inhibition can be improved, when the structural modifications are carried out on the suitable positions of A ring, B ring and C ring of flavonoid molecules using the substituent groups that have the strong electron-donating ability and can lower the molecular hydration energies of flavonoids. According to the results （33 compounds） obtained from the structural modifications for the luteolin molecule, we suggest the possible mechanisms for the inhibition of MMP-9 by flavonoids, and design the eight MMP-9 inhibitors whose biological activities are obviously improved by the structural modifications, which are expected to be confirmed experimentally.
出处
《化学学报》
SCIE
CAS
CSCD
北大核心
2011年第4期383-392,共10页
Acta Chimica Sinica
基金
中国药科大学人才引进基金(No.211078)资助项目
