Machine Learning Application for Medicinal Chemistry: Colchicine Case, New Structures, and Anticancer Activity Prediction

Abstract

In the contemporary era, the exploration of machine learning (ML) has gained widespread attention and is being leveraged to augment traditional methodologies in quantitative structure–activity relationship (QSAR) investigations. The principal objective of this research was to assess the anticancer potential of colchicine-based compounds across five distinct cell lines. This research endeavor ultimately sought to construct ML models proficient in forecasting anticancer activity as quantified by the IC50 value, while concurrently generating innovative colchicine-derived compounds. The resistance index (RI) is computed to evaluate the drug resistance exhibited by LoVo/DX cells relative to LoVo cancer cell lines. Meanwhile, the selectivity index (SI) is computed to determine the potential of a compound to demonstrate superior efficacy against tumor cells compared to its toxicity against normal cells, such as BALB/3T3. We introduce a novel ML system adept at recommending novel chemical structures predicated on known anticancer activity. Our investigation entailed the assessment of inhibitory capabilities across five cell lines, employing predictive models utilizing various algorithms, including random forest, decision tree, support vector machines, k-nearest neighbors, and multiple linear regression. The most proficient model, as determined by quality metrics, was employed to predict the anticancer activity of novel colchicine-based compounds. This methodological approach yielded the establishment of a library encompassing new colchicine-based compounds, each assigned an IC50 value. Additionally, this study resulted in the development of a validated predictive model, capable of reasonably estimating IC50 values based on molecular structure input.