ADME Evaluation in Drug Discovery.9.Prediction of Oral Bioavailability in Humans Based on Molecular Properties and Structural Fingerprints
Oral bioavailability is an essential parameter in drug screening cascades and a good indicator of the capability of the delivery of a given compound to the systemic circulation by oral administration.In the present work,we report a database of oral bioavailability of 1014 molecules determined in humans.A systematic examination of the relationships between various physicochemical properties and oral bioavailability were carried out to investigate the influence of these properties on oral bioavailability.A number of property-based rules for bioavailability classification were generated and evaluated.We found that no rule was an effective predictor for oral bioavailability because these simple rules cannot characterize the influence of important metabolic processes on bioavailability.Finally,the genetic function approximation (GFA) technique was employed to construct the multiple linear regression models for oral bioavailability using structural fingerprints as the basic parameters,together with several important molecular properties.The best model is able to predict human oral bioavailability with an r of 0.79,a q of 0.72,and a RMSE (root-mean-square error) of 22.30% of the compounds from the training set.The analysis of the descriptors chosen by GFA shows that the important structural fingerprints are primarily rehted to important intestinal absorption and well-known metabolic processes.The predictive power of the models was further evaluated using a separate test set of80 compounds,and the consensus modal can predict the oral bioavailability with rtest =0.71 and RMSE =23.5596 for the tested compounds.Since the necessary molecular properties and steal fingerprints can be calculated easily and quickly,the models we proposed here may help speed up the process of finding or designing compounds with improved oral bioavailability.
oral bioavailability ADME/T fingerprint genetic algorithm genetic function approximation intestinal absorption
Sheng Tian Youyong Li Junmei Wang Jian Zhang Tingjun Hou
Institute of Functional Nano & Soft Materials(FUNSOM)and Jiangsu Key Laboratory for Carbon.Based Fun Department of Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Bl The Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese M
国际会议
南京
英文
14-24
2012-05-13（万方平台首次上网日期，不代表论文的发表时间）