Identification of promising high-affinity inhibitors of SARS-CoV-2 main protease from African Natural Products Databases by Virtual Screening

Abstract

With the rapid spread of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen agent of COVID-19 pandemic created a serious threat to global public health, requiring the most urgent research for potential therapeutic agents. The availability of genomic data of SARS-CoV-2 and efforts to determine the protein structure of the virus facilitated the identification of potent inhibitors by using structure-based approach and bioinformatics tools. Many pharmaceuticals have been proposed for the treatment of COVID-19, although their effectiveness has not been assessed yet. However, it is important to find out new-targeted drugs to overcome the resistance concern. Several viral proteins such as proteases, polymerases or structural proteins have been considered as potential therapeutic targets. But the virus target must be essential for host invasion match some drugability criterion. In this Work, we selected the highly validated pharmacological target main protease M^pro and we performed high throughput virtual screening of African Natural Products Databases such as NANPDB, EANPDB, AfroDb, and SANCDB to identify the most potent inhibitors with the best pharmacological properties. In total, 8753 natural compounds were virtually screened by AutoDock vina against the main protease of SARS-CoV-2. Two hundred and five (205) compounds showed high-affinity scores (less than - 10.0 Kcal/mol), while fifty-eight (58) filtered through Lipinski's rules showed better affinity than known M^pro inhibitors (i.e., ABBV-744, Onalespib, Daunorubicin, Alpha-ketoamide, Perampanel, Carprefen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin, Ethyl biscoumacetate…). Those promising compounds could be considered for further investigations toward the developpement of SARS-CoV-2 drug development.

Keywords: African Natural Products; Main Protease; SARS-CoV-2; Virtual Screening.

Figure 1

Binding pocket (Red surface) of SARS-CoV-2 M^pro determined by CASTp server (left), highlighted in the Grid box, AutoDockTools (right) highlights also the two chains of the protein (chain A in purple and chain B in green).

Figure 2

Details of M^pro interactions with top four potential inhibitors: - top left, Sphaeropsidin A; - top right, Gypsogenic acid; - bottom left, Yardenone (SANC00595); and - bottom right, A-homo-3a-oxa-5beta-olean-12-en-3- one-28-oic acid. The ligands are illustrated in green stick surrounded by polar residues (magenta) establishing hydrogen bonds(yellow) with the protein and non-polar residues (cyan). M^pro is illustrated according to its different domains: domain I in Medium Blue; domain II in Yellow; domain III in red, the catalytic dyad in surface representation (Forest green). A long loop connects domain II to the domain III C-terminal (Magenta).