Context: With the wide application of deep learning in drug research and development, de novo molecular design methods based on recurrent neural network (RNN) have strong advantages in drug molecule generation. The RNN model can be used to learn the internal chemical structure of molecules, which is similar to a natural language processing task. Although techniques for generating target-specific molecular libraries based on RNN models are mature, research related to drug design and screening continues around the clock. Research based on de novo drug design methods to generate larger quantities of valid compounds is necessary.

Methods: In this study, a molecular generation model based on RNN was designed, which abandoned the traditional way of stacked RNN and introduced the Nested long short-term memory network structure. To enrich the library of focused molecules for specific targets, we fine-tuned the model using active molecules from novel coronavirus pneumonia and screened the molecules using machine learning models. Following rigorous screening, the selected molecules underwent molecular docking with the SARS-CoV-2 M-pro receptor using AutoDock2.4 to identify the top 3 potential inhibitors. Subsequently, 100-ns molecular dynamics simulations were conducted using Amber22. Molecule parameterization involved the GAFF2 force field, while the proteins were modeled using the ff19SB force field, with solvation facilitated by a truncated octahedral TIP3P solvent environment. Upon completion of molecular dynamics simulations, stability of ligand-protein complexes was assessed by analysis of RMSD, H-bonds, and MM-GBSA. Reasonable results prove that the model can complete the task of de novo drug design and has the potential to be ideal drug molecules.