Artesunate induces substantial topological alterations in the SARS-CoV-2 Nsp1 protein structure.

The need for novel antiviral treatments for coronavirus disease 2019 (COVID-19) continues with the widespread infections and fatalities throughout the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the deadly disease, relies on the non-structural protein Nsp1 for multiplication within the host cells and disarms the host immune defences by various mechanisms. Herein, we investigated the potential of artemisinin and its derivatives as possible inhibitors of SARS-CoV-2 Nsp1 through various computational approaches. Molecular docking results show that artemisinin (CID68827) binds to Nsp1 with a binding energy of -6.53 kcal/mol and an inhibition constant of 16.43 µM. The top 3 derivatives Artesunate (CID6917864), Artemiside (CID53323323) and Artemisone (CID11531457) show binding energies of -7.92 kcal/mol, -7.46 kcal/mol and -7.36 kcal/mol respectively. Hydrophobic interactions and hydrogen bonding with Val10, Arg11, and Gln50 helped to stabilize the protein-ligand complexes. The pharmacokinetic properties of these molecules show acceptable properties. The geometric parameters derived from large-scale MD simulation studies provided insights into the changes in the structural topology of Nsp1 upon binding of Artesunate. Thus, the findings of our research highlight the importance of artemisinin and its derivatives in the development of drugs to inhibit SARS-CoV-2 Nsp1 protein.

In silico analyses of major active constituents of fingerroot (Boesenbergia rotunda) unveils inhibitory activities against SARS-CoV-2 main protease enzyme.

Boesenbergia rotunda (L.) Mansf., commonly known as fingerroot is a perennial herb in the Zingiberaceae family with anticancer, anti-leptospiral, anti-inflammatory, antioxidant, antiulcer, and anti-herpes viral activities. While the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibitory activity of B. rotunda extract has been recently found, the active compounds contributing to this activity are yet unknown. The main protease (Mpro) enzyme is one of the most well established therapeutic targets among coronaviruses which plays a vital role in the maturation and cleavage of polyproteins during viral replication. The current work aims to identify active phytochemical substances from B. rotunda extract that can inhibit the replication of SARS-CoV-2 by using a combined molecular docking and dynamic simulation approaches. The virtual screening experiment revealed that fifteen molecules out of twenty-three major active compounds in the plant extract have acceptable drug-like characteristics. Alpinetin, Pinocembrin, and Pinostrobin have binding energies of -7.51 kcal/mol, -7.21 kcal/mol, and -7.18 kcal/mol, respectively, and can suppress Mpro activity. The stability of the simulated complexes of the lead compounds with the drug-receptor is demonstrated by 100-ns MD simulations. The binding free energies study utilizing molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA) show that the compounds and Mpro enzyme have favourable thermodynamic interactions, which are majorly driven by van der Waals forces. Thus, the selected bioactive phytochemicals from B. rotunda might be used as anti-SARS-CoV-2 candidates that target the Mpro enzyme.

Identification of SARS-CoV-2 inhibitors from extracts of Houttuynia cordata Thunb.

Houttuynia cordata Thunb., a perennial herb belonging to the Saururaceae family is a well-known ingredient of Traditional Chinese medicine (TCM) with several therapeutic properties. During the severe acute respiratory syndrome (SARS) outbreak in China, it was one of the approved ingredients in SARS preventative formulations and therefore, the plant may contain novel bioactive chemicals that can be used to suppress the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus for which there are currently no effective drugs available. Like all RNA viruses, SARS-CoV-2 encode RNA-dependent RNA polymerase (RdRp) enzyme which aids viral gene transcription and replication. The present study is aimed at understanding the potential of bioactive compounds from H. cordata as inhibitors of the SARS-CoV-2 RdRp enzyme. We investigated the drug-likeness of the plant's active constituents, such as alkaloids, polyphenols, and flavonoids, as well as their binding affinity for the RdRp enzyme. Molecular docking experiments show that compounds 3 (1,2,3,4,5-pentamethoxy-dibenzo-quinolin-7-one), 14 (7-oxodehydroasimilobine), and 21 (1,2-dimethoxy-3-hydroxy-5-oxonoraporphine) have a high affinity for the drug target and that the complexes are maintained by hydrogen bonds with residues like Arg553, Cys622 and Asp623, as well as hydrophobic interactions with other residues. The lead compounds' complexes with the target enzyme remained stable throughout the molecular dynamics simulation. Analysis of molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA) revealed the key residues contributing considerably to binding free energy. Thus, the findings reveal the potential of H. cordata bioactive compounds as anti-SARS-CoV-2 drug candidate molecules against the target enzyme.