Design of SARS-CoV-2 Mpro, PLpro Dual-Target Inhibitors Based on Deep Reinforcement Learning and Virtual Screening

Abstract

<b>Background:</b> Since December 2019, SARS-CoV-2 has continued to spread rapidly around the world. The effective drugs may provide a long-term strategy to combat this virus. The main protease (Mpro) and papain-like protease (PLpro) are two important targets for the inhibition of SARS-CoV-2 virus replication and proliferation. <b>Materials & methods:</b> In this study, deep reinforcement learning, covalent docking and molecular dynamics simulations were used to identify novel compounds that have the potential to inhibit both Mpro and PLpro. <b>Results & conclusion:</b> Three compounds were identified that can effectively occupy the Mpro protein cavity with the PLpro protein cavity and form high-frequency contacts with key amino acid residues (Mpro: His41, Cys145, Glu166; PLpro: Cys111). These three compounds can be further investigated as potential lead compounds for SARS-CoV-2 inhibitors.