AI-driven covalent drug design strategies targeting main protease (mpro) against SARS-CoV-2: structural insights and molecular mechanisms

Abstract

The emergence of new SARS-CoV-2 variants has raised concerns about the effectiveness of COVID-19 vaccines. To address this challenge, small-molecule antivirals have been proposed as a crucial therapeutic option. Among potential targets for anti-COVID-19 therapy, the main protease (Mpro) of SARS-CoV-2 is important due to its essential role in the virus’s life cycle and high conservation. The substrate-binding region of the core proteases of various coronaviruses, including SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV), could be used for the generation of new protease inhibitors. Various drug discovery methods have employed a diverse range of strategies, targeting both monomeric and dimeric forms, including drug repurposing, integrating virtual screening with high-throughput screening (HTS), and structure-based drug design, each demonstrating varying levels of efficiency. Covalent inhibitors, such as Nirmatrelvir and MG-101, showcase robust and high-affinity binding to Mpro, exhibiting stable interactions confirmed by molecular docking studies. Development of effective antiviral drugs is imperative to address potential pandemic situations. This review explores recent advances in the search for Mpro inhibitors and the application of artificial intelligence (AI) in drug design. AI leverages vast datasets and advanced algorithms to streamline the design and identification of promising Mpro inhibitors. AI-driven drug discovery methods, including molecular docking, predictive modeling, and structure-based drug repurposing, are at the forefront of identifying potential candidates for effective antiviral therapy. In a time when COVID-19 potentially threat global health, the quest for potent antiviral solutions targeting Mpro could be critical for inhibiting the virus. Communicated by Ramaswamy H. Sarma