Yang Ha

John Ho, Zhao-Heng Yin, Colin Zhang et al.

Predicting the solubility of given molecules remains crucial in the pharmaceutical industry. In this study, we revisited this extensively studied topic, leveraging the capabilities of contemporary computing resources. We employed two machine learning models: a linear regression model and a graph convolutional neural network (GCNN) model, using various experimental datasets. Both methods yielded reasonable predictions, with the GCNN model exhibiting the highest level of performance. However, the present GCNN model has limited interpretability while the linear regression model allows scientists for a greater in-depth analysis of the underlying factors through feature importance analysis, although more human inputs and evaluations on the overall dataset is required. From the perspective of chemistry, using the linear regression model, we elucidated the impact of individual atom species and functional groups on overall solubility, highlighting the significance of comprehending how chemical structure influences chemical properties in the drug development process. It is learned that introducing oxygen atoms can increase the solubility of organic molecules, while almost all other hetero atoms except oxygen and nitrogen tend to decrease solubility.

Colin Zhang, Yang Ha

Multiple sclerosis (MS) is a debilitating neurological disease affecting nearly one million people in the United States. Sphingosine-1-phosphate receptor 1, or S1PR1, is a protein target for MS. Siponimod, a ligand of S1PR1, was approved by the FDA in 2019 for MS treatment, but there is a demonstrated need for better therapies. To this end, we finetuned an autoencoder machine learning model that converts chemical formulas into mathematical vectors and generated over 500 molecular variants based on siponimod, out of which 25 compounds had higher predicted binding affinity to S1PR1. The model was able to generate these ligands in just under one hour. Filtering these compounds led to the discovery of six promising candidates with good drug-like properties and ease of synthesis. Furthermore, by analyzing the binding interactions for these ligands, we uncovered several chemical properties that contribute to high binding affinity to S1PR1. This study demonstrates that machine learning can accelerate the drug discovery process and reveal new insights into protein-drug interactions.