Andrews C W, Bennett L, Yu L X
GlaxoWellcome Inc., Research Triangle Park, North Carolina 27709, USA.
Pharm Res. 2000 Jun;17(6):639-44. doi: 10.1023/a:1007556711109.
The purpose of this investigation was to develop a quantitative structure-bioavailability relationship (QSBR) model for drug discovery and development.
A database of drugs with human oral bioavailability was assembled in electronic form with structure in SMILES format. Using that database, a stepwise regression procedure was used to link oral bioavailability in humans and substructural fragments in drugs. The regression model was compared with Lipinski's Rule of Five.
The human oral bioavailability database contains 591 compounds. A regression model employing 85 descriptors was built to predict the human oral bioavailability of a compound based on its molecular structure. Compared to Lipinski's Rule of Five, the false negative predictions were reduced from 5% to 3% while the false positive predictions decreased from 78% to 53%. A set of substructural descriptors was identified to show which fragments tend to increase/decrease human oral bioavailability.
A novel quantitative structure-bioavailability relationship (QSBR) was developed. Despite a large degree of experimental error, the model was reasonably predictive and stood up to cross-validation. When compared to Lipinski's Rule of Five, the QSBR model was able to reduce false positive predictions.
本研究的目的是开发一种用于药物发现和开发的定量结构-生物利用度关系（QSBR）模型。
以电子形式收集了具有人体口服生物利用度的药物数据库，其结构采用SMILES格式。利用该数据库，采用逐步回归程序将人体口服生物利用度与药物中的亚结构片段联系起来。将回归模型与Lipinski的五规则进行比较。
人体口服生物利用度数据库包含591种化合物。建立了一个使用85个描述符的回归模型，以根据化合物的分子结构预测其人体口服生物利用度。与Lipinski的五规则相比，假阴性预测从5%降至3%，而假阳性预测从78%降至53%。确定了一组亚结构描述符，以显示哪些片段倾向于增加/降低人体口服生物利用度。
开发了一种新型的定量结构-生物利用度关系（QSBR）。尽管存在很大程度的实验误差，但该模型具有合理的预测能力，并经得起交叉验证。与Lipinski的五规则相比，QSBR模型能够减少假阳性预测。
