Drug-likeness Analysis of Traditional Chinese Medicines: Prediction of Drug-likeness Using Machine Learning Approaches

Quantitative or qualitative characterization of the drug-like features of known drugs may help medicinal and computational chemists to select higher quality drug leads from a huge pool of compounds and to improve the efficiency of drug design pipelines. For this purpose, the theoretical models for drug-likeness to discriminate between drug-like and non-drug-like based on molecular physicochemical properties and structural fingerprints were developed by using the naive Bayesian classification (NBC) and recursive partitioning (RP) techniques, and then the drug-likeness of the compounds from the Traditional Chinese Medicine Compound Database (TCMCD) was evaluated. First, the impact of molecular physicochemical properties and structural fingerprints on the prediction accuracy of drug-likeness was examined. We found that, compared with simple molecular properties, structural fingerprints were more essential for the accurate prediction of drug-likeness. Then, a variety of Bayesian classifiers were constructed by changing the ratio of drug-like to non-drug-like molecules and the size of the training set. The results indicate that the prediction accuracy of the Bayesian classifiers was closely related to the size and the degree of the balance of the training set. When a balanced training set was used, the best Bayesian classifier based on 21 physicochemical properties and the LCFP_6 fingerprint set yielded an overall leave-one-out (LOO) cross-validated accuracy of 91.4% for the 140,000 molecules in the training set and 90.9% for the 40,000 molecules in the test set. In addition, the RP classifiers with different maximum depth were constructed and compared with the Bayesian classifiers, and we found that the best Bayesian classifier outperformed the best RP model with respect to overall prediction accuracy. Moreover, the Bayesian classifier employing structural fingerprints highlights the important substructures favorable or unfavorable for drug-likeness, offering extra valuable information for getting high quality lead compounds in the early stage of the drug design/discovery process. Finally, the best Bayesian classifier was used to predict the drug-likeness of 33,961 compounds in TCMCD. Our calculations show that 59.37% of the molecules in TCMCD were identified as drug-like molecules, indicating that traditional Chinese medicines (TCMs) are therefore an excellent source of drug-like molecules. Furthermore, the important structural fingerprints in TCMCD were detected and analyzed. Considering that the pharmacology of TCMCD and MDDR (MDL Drug Data Report) was linked by the important common structural features, the potential pharmacology of the compounds in TCMCD may therefore be annotated by these important structural signatures identified from Bayesian analysis, which may be valuable to promote the development of TCMs.