Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic...Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.展开更多
番石榴叶提取物降糖效果明显,但确切活性成分和作用机制尚不清楚.文中采用Discovery Studio 2.1软件的CDOCKER模块,以番石榴叶中分离得到的和已知的三萜皂苷、黄酮和鞣质类32个小分子化合物作为配体,分别与治疗糖尿病相关的PTP1B、PPAR...番石榴叶提取物降糖效果明显,但确切活性成分和作用机制尚不清楚.文中采用Discovery Studio 2.1软件的CDOCKER模块,以番石榴叶中分离得到的和已知的三萜皂苷、黄酮和鞣质类32个小分子化合物作为配体,分别与治疗糖尿病相关的PTP1B、PPARγ、α-淀粉酶以及α-葡萄糖苷酶这4个生物活性的酶/受体进行分子对接,并将对接结果进行打分,评判配体与酶/受体的结合模式与亲和力,从而进行番石榴叶中活性小分子的虚拟筛选,揭示可能的作用机制.结果显示,黄酮类和鞣质类化合物与PTP1B和PPARγ的结合活性较高,该类化合物与酶/受体活性部位通过疏水作用和氢键相互结合.因此,在活性成分的立体结构改造中引入疏水基团,将提高其与PTP1B和PPARγ对接的亲和力.展开更多
基金Supported by the Natural Science Foundation of Guangxi Province(Nos.2013GXNSFAA019019 and 2013GXNSFAA019041)
文摘Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.
文摘番石榴叶提取物降糖效果明显,但确切活性成分和作用机制尚不清楚.文中采用Discovery Studio 2.1软件的CDOCKER模块,以番石榴叶中分离得到的和已知的三萜皂苷、黄酮和鞣质类32个小分子化合物作为配体,分别与治疗糖尿病相关的PTP1B、PPARγ、α-淀粉酶以及α-葡萄糖苷酶这4个生物活性的酶/受体进行分子对接,并将对接结果进行打分,评判配体与酶/受体的结合模式与亲和力,从而进行番石榴叶中活性小分子的虚拟筛选,揭示可能的作用机制.结果显示,黄酮类和鞣质类化合物与PTP1B和PPARγ的结合活性较高,该类化合物与酶/受体活性部位通过疏水作用和氢键相互结合.因此,在活性成分的立体结构改造中引入疏水基团,将提高其与PTP1B和PPARγ对接的亲和力.
