Identification of Active Molecules against Thrombocytopenia through Machine Learning

• Published in: Journal of chemical information and modeling 2024-08, Vol.64 (16), p.6506-6520
• Main Authors: Yang, Youyou, Gan, Wenli, Lin, Lei, Wang, Long, Wu, Jianming, Luo, Jiesi
• Format: Article
• Language: English
• Subjects: Accuracy; Algorithms; Chemical Information; Machine learning; Molecular properties; Pharmacology; Thrombocytopenia; Traditional Chinese medicine
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.4c00718

Thrombocytopenia, which is associated with thrombopoietin (TPO) deficiency, presents very limited treatment options and can lead to life-threatening complications. Discovering new therapeutic agents against thrombo­cytopenia has proven to be a challenging task using traditional screening approaches. Fortunately, machine learning (ML) techniques offer a rapid avenue for exploring chemical space, thereby increasing the likelihood of uncovering new drug candidates. In this study, we focused on computational modeling for drug-induced megakaryocyte differentiation and platelet production using ML methods, aiming to gain insights into the structural characteristics of hemato­poietic activity. We developed 112 different classifiers by combining eight ML algorithms with 14 molecule features. The top-performing model achieved good results on both 5-fold cross-validation (with an accuracy of 81.6% and MCC value of 0.589) and external validation (with an accuracy of 83.1% and MCC value of 0.642). Additionally, by leveraging the Shapley additive explanations method, the best model provided quantitative assessments of molecular properties and structures that significantly contributed to the predictions. Furthermore, we employed an ensemble strategy to integrate predictions from multiple models and performed in silico predictions for new molecules with potential activity against thrombo­cytopenia, sourced from traditional Chinese medicine and the Drug Repurposing Hub. The findings of this study could offer valuable insights into the structural characteristics and computational prediction of thrombopoiesis inducers.