کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
7562498 | 1491509 | 2017 | 39 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
ADME properties evaluation in drug discovery: Prediction of plasma protein binding using NSGA-II combining PLS and consensus modeling
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آنالیزی یا شیمی تجزیه
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چکیده انگلیسی
Plasma protein binding affinity of a drug compound has a strong influence on its pharmacodynamic behavior because it can affect the drug uptake and distribution. In this study, we collected a sizeable dataset consisting of 1830 drug compounds from several accessible sources. A descriptor pool composed of four different types of descriptors (2-D, 3-D, Estate and MACCS) was firstly built and non-dominated sorting genetic algorithm (NSGA-II) combining partial least square (PLS) regression was applied to select important descriptors for model building. Finally, we obtained a consensus model (for five-fold cross-validation: Q2 = 0.750; RMSE = 16.151) based on five different predictive models built using random forest (RF), support vector machine (SVM), Cubist, Gaussian process (GP), and Boosting. Further, a test set and two external validation datasets were applied to validate its robustness and practicality. For the test set, RT2 = 0.787 and RMSET = 14.154; when two external datasets were applied, REx2 = 0.704 and 0.703, RMSEEx = 18.194 and 17.233 respectively. Additionally, according to OECD principles, y-randomization, Williams plot and scaffold analyses were proposed to validate the reliability and practical application domain of our predictive model. Overall, our consensus model shows a good prediction performance and generalization ability in predicting plasma protein binding (PPB). After analyzing those important descriptors selected by NSGA-II and RF, we concluded that the PPB of a drug compound is mainly related to its lipophilicity, aromatic rings, and partial charge properties. In summary, this study developed a robust and practical consensus model for PPB prediction and it could be used to the distribution evaluation and risk assessment in the early stage of drug development.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Chemometrics and Intelligent Laboratory Systems - Volume 170, 15 November 2017, Pages 84-95
Journal: Chemometrics and Intelligent Laboratory Systems - Volume 170, 15 November 2017, Pages 84-95
نویسندگان
Ning-Ning Wang, Zhen-Ke Deng, Chen Huang, Jie Dong, Min-Feng Zhu, Zhi-Jiang Yao, Alex F. Chen, Ai-Ping Lu, Qi Mi, Dong-Sheng Cao,