ABSTRACT
Three new hexadepsipeptides (1-3), along with beauvericin (4), beauvericin D (5), and four 4-hydroxy-2-pyridone derivatives (6-9) were isolated from the endophytic fungus Fusarium sp. CPCC 400857 that derived from the stem of tea plant. Their structures were determined by extensive 1D and 2D NMR, and HRESIMS analyses. The absolute configuration of hexadepsipeptides were elucidated by the advanced Marfey's method and chiral HPLC analysis. Compounds 4, and 7-9 displayed the cytotoxicity against human pancreatic cancer cell line, AsPC-1 with IC50 values ranging from 3.45 to 29.69 µM, and 7 and 8 also showed the antiviral activity against the coronavirus (HCoV-OC43) with IC50 values of 13.33 and 6.65 µM, respectively.
ABSTRACT
Presently, the prime global focus is on SARS-CoV-2, as no fully established, licensed medicine has been found thus far, in spite of the existence of various reports and administration of partially proven certain class of natural products. However, in case of natural products, the extraction and purification limit their application. This situation drives researchers to explore synthetically viable drugs. In the present investigation, twenty-three 2-pyridone synthetic derivatives (P1-P23) have been theoretically tested for their suitability as potential inhibitors for COVID-19 main protease through DFT, molecular docking, and molecular dynamics simulations. DFT calculations offer insights into structure-property relationships, while ADMET studies indicate the pharmacological characteristics of these molecules. Molecular docking studies ascertain the nature and mode of interactions of these entities with COVID-19 main protease. Furthermore, covalent docking has been carried out to verify the feasibility of the formation of a covalent bond with the active site. The top protein-inhibitor complexes, such as P18, P11, and P12, were identified based on their glide score. These molecules, along with the covalent docked complexes, namely P18 and P16, were selected and subjected to molecular dynamics simulations. The 100 ns simulation process exhibited that the covalent docked ones, due to their stable form could serve as lead compounds against SARS-CoV-2. Hence, this study affirms the potential candidature of 2-pyridone-based inhibitors.
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 (Mpro) 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 Mpro. A search for natural, antimicrobial products with the 2-pyridone moiety was undertaken herein, and their calculated potency as inhibitors of SARS-CoV-2 Mpro 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 (Ki values) for each 2-pyridone-containing compound with SARS-CoV-2 Mpro. This consisted of molecular optimization of the 2-pyridone compound, docking of the compound with a crystal structure of SARS-CoV-2 Mpro, and evaluation of the predicted interactions and ligand-enzyme conformations. All compounds investigated bound to the active site of SARS-CoV-2 Mpro, close to the catalytic dyad (His-41 and Cys-145). Thirteen molecules had predicted Ki 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 Mpro and with desirable drug-like properties, which may lead to the rapid discovery of a treatment for COVID-19.