Exploring the potential of machine learning to design antidiabetic molecules: a comprehensive study with experimental...

Recent advances in hardware and software algorithms have led to the rise of data-driven approaches for designing therapeutic modalities. One of the major causes of human mortality is diabetes. Thus, there is a tremendous opportunity for research into effective antidiabetic designs. Therefore, in this study, we used machine learning-based small molecule design. We used various chemoinformatic and binary fingerprint techniques on small molecules to construct multiple models for alpha-amylase inhibitors. Among these models, the top models were used for ensemble-based machine learning predictions on libraries of organic molecules supplemented with synthetic scaffolds that could be used as antidiabetic agents. Further, involved identifying 10 promising molecules from computational studies and determining their inhibitory effects on alpha-amylase. These molecules were synthesised and thoroughly analysed to assess their biological inhibitory properties. Then, thermodynamic simulations were conducted to determine the stability and affinity of experimentally active molecules. The research results showcased the top 10 ML models recorded impressive statistics with an average model score of 0.8216, Pearson-r value of 0.827 and external validation yielding a Q² value of 0.835, proving their reliability and accuracy. Ten derivatives of benzothiophene dioxolane was prime research focus due to computational predictions. The biological inhibitory assay of synthesised molecules showed that small molecules with ID ALC5 and ALC6 exhibited inhibitory efficiencies (IC₅₀) of 2.1 ± 0.14 µM and 5.71 ± 0.02 µM against alpha-amylase enzyme, whereas other molecules showed moderate inhibition. In conclusion, the positive results of the experiment indicate that researchers should explore machine learning-driven design.Communicated by Ramaswamy H. Sarma.