Molecule generation toward target protein (SARS-CoV-2) using reinforcement learning-based graph neural network via knowledge graph

AI-driven approaches are widely used in drug discovery, where candidate molecules are generated and tested on a target protein for binding affinity prediction. However, generating new compounds with desirable molecular properties such as Quantitative Estimate of Drug-likeness (QED) and Dopamine Receptor D2 activity (DRD2) while adhering to distinct chemical laws is challenging. To address these challenges, we proposed a graph-based deep learning framework to generate potential therapeutic drugs targeting the SARS-CoV-2 protein. Our proposed framework consists of two modules: a novel reinforcement learning (RL)-based graph generative module with knowledge graph (KG) and a graph early fusion approach (GEFA) for binding affinity prediction. The first module uses a gated graph neural network (GGNN) model under the RL environment for generating novel molecular compounds with desired properties and a custom-made KG for molecule screening. The second module uses GEFA to predict binding affinity scores between the generated compounds and target proteins. Experiments show how fine-tuning the GGNN model under the RL environment enhances the molecules with desired properties to generate 100%\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$100\%$$\end{document} valid and 100%\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$100\%$$\end{document} unique compounds using different scoring functions. Additionally, KG-based screening reduces the search space of generated candidate molecules by 96.64%\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$96.64\%$$\end{document} while retaining 95.38%\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$95.38\%$$\end{document} of promising binding molecules against SARS-CoV-2 protein, i.e., 3C-like protease (3CLpro). We achieved a binding affinity score of 8.185 from the top rank of generated compound. In addition, we compared top-ranked generated compounds to Indinavir on different parameters, including drug-likeness and medicinal chemistry, for qualitative analysis from a drug development perspective.