Generative adversarial network (GAN) model-based design of potent SARS-CoV-2 Mpro inhibitors using the electron density of ligands and 3D binding pockets: insights from molecular docking, dynamics simulation, and MM-GBSA analysis.

Deep learning-based generative adversarial network (GAN) frameworks have recently been developed to expedite the drug discovery process. These models generate novel molecules from scratch and validate them through molecular docking simulation to identify the most promising candidates for a given drug target. In this study, the SARS-CoV-2 main protease (M^pro) was selected as the drug target. Two distinct GAN algorithms were employed to generate novel small molecules. One approach utilized experimental electron density (ED-based) data of ligands for training to generate drug-like molecules, while the second approach leveraged the target binding pocket to capture spatial and bonding relationship between atoms within the binding pockets. The ED-based approach generated approximately 26,000 molecules, whereas the binding pocket-based method produced around 100 molecules. These generated molecules were subsequently ranked based on molecular docking results using the glide XP score (both flexible and rigid docking) and AutoDock Vina. To identify the most potent GAN-derived molecules, molecular docking was also performed on co-crystallized inhibitor molecules of M^pro. The six most promising molecules from these GAN approaches were further evaluated for stability, interactions, and MM-GBSA binding free energy through molecular dynamics simulations. This analysis led to the identification of four potent M^pro inhibitor molecules, all featuring a 2-benzyl-6-bromophenol scaffold. The binding free energies of these compounds were compared with those of other M^pro inhibitors, revealing that our compounds demonstrated better affinity for M^pro than some broad-spectrum protease inhibitors. The dynamic cross-correlation matrix plot indicated strongly correlated and anti-correlated regions, potentially linked to ligand binding.