Hexahydropyrrolo-[2,3-b]-indole Containing Alkaloids as a SARS-CoV-2 Inhibitors: An Integrated Multi-Target Based in-silico Approach

The discovery of potential drug molecules which can inhibit multiple targets at a single shot is extremely efficient in combating modern diseases. In continuation of this effort, this manuscript represents a multi-targeted based virtual screening approach aimed at identifying the most promising natural alkaloids based on Hexahydropyrrolo-[2,3-b]-indole backbone as a potential inhibitor against SARS-CoV-2. In this pursuit, eight traditional and understudied SARS-CoV-2 viral targets like the main protease (Mpro), RNA polymerase (RdRp), Envelope protein (Evp), Receptor binding domain (S-RBD), Human receptor angiotensin (hACE2), Spike protein, uridine specific endoribonuclease (nsp15) and capping protein (nsp16) are selected. The virtual screening of a series of naturally occurring alkaloids across these eight binding sites of SARS-CoV-2 proteins demonstrated great binding affinity. In fact, these sets of small natural product molecules highlight similar or greater binding affinity with multiple proteins compared to traditional-approved drugs like Ramdesivir, Nirmatrelvir and Molnupiravir. Based on the ADMET profiling, it can be verified that these sets of natural products exhibit the optimal pharmacokinetic parameters. Furthermore, analysis of the key amino acid-ligand interactions and time-dependent DFT calculation of top leads support the possibility of the multi-targeting capability of these moieties to fight persistently against the rapidly evolving SARS-CoV-2.