COVID-19, caused by SARS-CoV-2, is a highly contagious disease with significant transmissibility and pathogenicity. The main protease of SARS-CoV-2 (M^pro or 3CL^pro) is crucial for viral replication, making it a key therapeutic target. Nirmatrelvir, a promising M^pro inhibitor, contains a trifluoroacetyl group in its P4 fragment, which presents opportunities for further optimization. This study aims to enhance the inhibitory activity of nirmatrelvir through structural modification of the P4 fragment. Using a computer-aided drug design (CADD) approach, 11 novel compounds were identified based on molecular docking scores, binding free energy, predicted ADMET properties, structural diversity, synthetic feasibility, and inhibitory activity. IC₅₀ measurements and molecular dynamics (MD) simulations demonstrated significant inhibitory potential for most compounds, with IC₅₀ values ranging from 0.0435-0.9989 μM. Notably, compounds 2-5a and 2-5f exhibited inhibitory activity against SARS-CoV-2 M^pro comparable to that of nirmatrelvir. These findings offer valuable insights for the development of anti-SARS-CoV-2 therapeutics.

2025-03-19·Natural Product Research

Evaluation of natural products from virtual screenings as SARS-CoV-2 main protease inhibitors using combinational experiments

Article

作者: Liu, Xiaoping ; Chen, Yunyu ; Shang, Chao ; Zhou, Jiahao ; Zhang, Rui ; Yan, Haohao

Recently, andrographolide, kaempferol, maslinic acid, rutin, and schaftoside have been identified as potent SARS-CoV-2 main protease (Mpro) inhibitors via molecular docking studies. However, no comprehensive in vitro testing of these compounds against Mpro has been conducted. In this study, we rigorously evaluated the in vitro inhibition of Mpro by these compounds using combinational experiments, including fluorescence resonance energy transfer (FRET), fluorescence polarization (FP), and dimerization-dependent red fluorescent protein (ddRFP) assays. Our data revealed that these compounds are not Mpro inhibitors based on the results from a set of in vitro assays. These results suggest that an efficient combination of a molecular docking approach and an experimental assay is essential for the discovery of Mpro inhibitors in the future.

2024-06-13·Journal of Medicinal Chemistry

Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs

Article

作者: Si, Yaoyao ; Claff, Tobias ; Kawaguchi, Atsushi ; Voget, Rabea ; Ogura, Yukino ; Gütschow, Michael ; Sylvester, Katharina ; Krasniqi, Vesa ; Wolf, Valentina ; Sträter, Norbert ; Useini, Abibe ; Breidenbach, Julian ; Hingst, Alexandra ; Müller, Christa E

Given the crucial role of the main protease (M^pro) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M^pro. Our systematic approach combined an M^pro active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent M^pro inhibitor 84 with an IC₅₀ value of 3.23 nM and a second-order rate constant of inactivation, k_inac/K_i, of 448,000 M^-1s^-1. The open-chain M^pro inhibitor 58, along with the macrocyclic compounds 83 and 84, a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC₅₀ values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic M^pro inhibitors as anti-SARS-CoV-2 agents.

100 项与 SARS-CoV-2 Mpro inhibitors(University of Bonn) 相关的药物交易

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