摘要
目的:从极性原子净电荷预测药物在人体小肠中的吸收百分数和透过Caco-2单细胞层的渗透系数。方法:用分子力学MM+法得到药物分子的优化几何构型,用M onte Carlo法计算分子体积,用半经验自洽场分子轨道CNDO/2法计算原子净电荷,相关分析采用逐步多元回归分析法。结果:药物分子在人体小肠中的吸收百分数和透过Caco-2单细胞层的渗透系数,均与氢键给体的原子净电荷之和(ΣQH)与氢键受体的原子净电荷之和(ΣQN,O)具有良好的相关性。氢键给体的正电荷和氢键受体的负电荷越多,药物分子在人体小肠中的吸收百分数和透过Caco-2单细胞层的渗透系数就越小。结论:药物在人体小肠中的吸收与其形成氢键能力密切相关。形成氢键能力弱的药物分子在人体小肠中的吸收较大。从极性原子净电荷参数预测药物在人体小肠中的吸收,具有方便快捷的优点,可用于候选口服药物的高通量筛选。
Objective： To predict human intestinal absorption and permeability coefficients in Caco-2 cell monolayers from net polar atomic charges of drug molecules. Methods： The net atomic charges and the volumes of drug molecules were obtained with the semiempirical self-consistent field molecular orbital calculation CNDO/2 method and Mont Carlo method respectively, using the minimum energy conformation obtained from the optimization of the standard molecular geometry with the molecular mechanics MM＋ method. The stepwise multiple regression analysis was used to obtain the correlation equations. Results： Both percent of human intestinal absorption and permeability coefficients in Caco-2 cell monolayers of drug molecules were well correlated with the sum of the net atomic charges of all hydrogen-bonding donors （∑QH）and the sum of the net atomic charges of all hydrogen-bonding acceptors （∑QN,O）. The more the net positive atomic charges of hydrogen-bonding donors and the net negative atomic charges of hydrogen-bonding acceptors, the less were the percent human intestinal absorption and permeability coefficients in Caco-2 cell monolayers of drug molecules. Conclusion： Drug absorption in human intestines is closely related with its hydrogen-bonding potential. The drug molecules with weaker hydrogen-bonding potential have greater percent human intestinal absorption. The net polar atomic charges can be computed simply, so they can be used in high throughput screening of oral drugs.
出处
《浙江大学学报（医学版）》
CAS
CSCD
2006年第2期199-203,共5页
Journal of Zhejiang University(Medical Sciences)
基金
国家自然科学基金项目(30371692)
关键词
肠吸收
药物吸收
小肠Caco-2细胞
氢键
Intestinal absorption
Drug absorption
Small intestine
Caco-2 cells
Hydrogen bond
