5/1/2023 0 Comments Unbound reality fragment![]() Structure-based docking algorithms can sample and score binding poses in seconds, making it possible to evaluate large libraries, and this approach is not restricted to compounds that are physically available. The determination of high-resolution crystal structures of SARS-CoV-2 proteins (14) has enabled virtual screening campaigns to identify hits that can be developed into antiviral drugs. (13) These libraries provide opportunities to identify potential therapeutic agents that can readily be synthesized and tested for activity but require development of effective strategies for navigation in this enormous chemical space. The size of commercial compound libraries is growing rapidly, and >10 billion make-on-demand molecules are currently available from chemical suppliers. (10−12) It was clear that development of safe and efficacious drugs targeting coronaviruses could benefit from the identification of novel noncovalent M pro inhibitors with more favorable properties. However, the noncovalent scaffolds were peptidomimetics, a chemotype that tends to have poor pharmacokinetic properties, and covalent modifiers typically require extensive optimization to modulate activity and selectivity. Prior to the COVID-19 pandemic, several compounds targeting M pro of coronaviruses via covalent (e.g., GC376 (7)) or noncovalent mechanisms (e.g., ML188 (5,8,9)) had been identified. Targeting proteases has been a successful strategy for infections caused by the human immunodeficiency and hepatitis C viruses, (6) but as M pro is structurally and mechanistically different, new inhibitors need to be developed for coronaviruses. (5) Inhibition of M pro blocks the processing of polyproteins produced by translation of the viral RNA, which is an essential step in SARS-CoV-2 replication. (4) Among the proteins encoded by the SARS-CoV-2 genome, the main protease (M pro) has emerged as a promising target. Attempts to repurpose approved drugs identified several promising candidates, (3) but in larger clinical studies most of these compounds (e.g., remdesivir and hydroxychloroquine) had little or no effect on mortality or the duration of hospitalization. In early 2020, major global efforts were initiated to develop drugs to treat coronavirus infections. Although the road to development of a drug may be long, discovery of inhibitors targeting coronavirus replication must be prioritized as such therapeutic agents can improve the quality of life of millions of patients worldwide. In this scenario, antiviral agents are needed to treat patients that have been infected as well as be given prophylactically to protect high-risk groups. (2) Analogous to common cold viruses, SARS-CoV-2 is expected to continue to circulate and remain a major threat to our society. Variants of SARS-CoV-2 for which the vaccines are less effective have already emerged, which is a strong indication that antiviral drugs are needed to complement vaccines in the long term. (1) Despite promising vaccination programs against COVID-19, antiviral drugs will likely be crucial to control the inevitable future outbreaks of coronaviruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the greatest health crisis of this generation and already led to >5 million deaths worldwide. Crystal structures of target–inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells. ![]() ![]() Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. One hundred top-ranked compounds were tested in binding and enzymatic assays. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. ![]() Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks.
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