2-Pyridone natural products as inhibitors of SARS-CoV-2 main protease

Abstract

The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease (M^pro) is an important enzyme for viral replication. Small molecules that inhibit this protease could lead to an effective COVID-19 treatment. The 2-pyridone scaffold was previously identified as a possible key pharmacophore to inhibit SARS-CoV-2 M^pro. A search for natural, antimicrobial products with the 2-pyridone moiety was undertaken herein, and their calculated potency as inhibitors of SARS-CoV-2 M^pro was investigated. Thirty-three natural products containing the 2-pyridone scaffold were identified from the literature. An in silico methodology using AutoDock was employed to predict the binding energies and inhibition constants (K_i values) for each 2-pyridone-containing compound with SARS-CoV-2 M^pro. This consisted of molecular optimization of the 2-pyridone compound, docking of the compound with a crystal structure of SARS-CoV-2 M^pro, and evaluation of the predicted interactions and ligand-enzyme conformations. All compounds investigated bound to the active site of SARS-CoV-2 M^pro, close to the catalytic dyad (His-41 and Cys-145). Thirteen molecules had predicted K_i values <1 μM. Glu-166 formed a key hydrogen bond in the majority of the predicted complexes, while Met-165 had some involvement in the complex binding as a close contact to the ligand. Prominent 2-pyridone compounds were further evaluated for their ADMET properties. This work has identified 2-pyridone natural products with calculated potent inhibitory activity against SARS-CoV-2 M^pro and with desirable drug-like properties, which may lead to the rapid discovery of a treatment for COVID-19.

Keywords: 2-Pyridone; AutoDock; COVID-19; In silico molecular modelling; Main protease (M(pro)); Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Fig. 1

The crystal structure of the SARS-CoV-2 main protease (M^pro) monomer (PDB: 6WQF) is comprised of three domains (I–III). The domains, amino acid residues of the catalytic site, His-41 (yellow), Cys-145 (skyblue) and embedded catalytic water molecule (red/white spheres) as suggested by Kneller et al. [23], are depicted. Figure was developed using PyMOL [43].

Fig. 2

The most potent 2-pyridone natural products, compounds 1–4 (A–D), are docked with SARS-CoV-2 main protease (M^pro) (PDB: 6WQF). The structures, binding energies and inhibition constants (K_i values) for 1–4 are summarized in Table 1, as well as their ADMET properties in Table 5. The H-bonding (dashed black lines) and close contact amino acid residues for 1–4 are depicted in their corresponding panel, as well as the catalytic dyad, His-41 (skyblue), Cys-145 (yellow), and embedded catalytic water (red/white spheres) as suggested by Kneller et al. [23]. Figures were generated using PyMOL [43].