Drug design of human dihydrofolate reductase (hDHFR) inhibitors with deep learning

Abstract

AbstractHuman dihydrofolate reductase (hDHFR) inhibitors have been a popular research object designed as anti‐cancer, anti‐malarial, and antibacterial drugs for decades. Besides quantitative structure‐activity relationship (QSAR), artificial intelligence (AI) has recently been introduced in numerous professional biological researches, such as molecular drug design and biological activity prediction. In this study, we construct a deep‐learning workflow for designing novel hDHFR inhibitors. This workflow mainly includes two networks, as described in the following: The first one is the artificial neural network trained by the molecules selected from the ChEMBL database with experimental hDHFR inhibitions as the label to evaluate the bioactivity of the designed molecular structures constructed from the second network. The second network utilizes conditional generative and adversarial networks (cGAN) to generate candidate molecules with the desired properties. Finally, the obtained candidate molecules with high hDHFR inhibition are subjected to a molecular docking process to verify their binding patterns and affinity strengths inside the active site of hDHFR. In the end, we have successfully identified several novel drug‐like compounds with hDHFR inhibition comparable to those currently used in clinics. We present a new tool to effectively design new drug‐like compounds through an AI approach.