Neoechinulin A as a Promising SARS-CoV-2 Mpro Inhibitor: In Vitro and In Silico Study Showing the Ability of Simulations in Discerning Active from Inactive Enzyme Inhibitors

Hani A Alhadrami,Gaia Burgio,Mostafa E Rateb,Mohammed Yaseen,Ahmed M Sayed,Suzan E Jiffri,Bathini Thissera,Raha Orfali

doi:10.3390/md20030163

Abstract

The COVID-19 pandemic and its continuing emerging variants emphasize the need to discover appropriate treatment, where vaccines alone have failed to show complete protection against the new variants of the virus. Therefore, treatment of the infected cases is critical. This paper discusses the bio-guided isolation of three indole diketopiperazine alkaloids, neoechinulin A (1), echinulin (2), and eurocristatine (3), from the Red Sea-derived Aspergillus fumigatus MR2012. Neoechinulin A (1) exhibited a potent inhibitory effect against SARS-CoV-2 Mpro with IC50 value of 0.47 μM, which is comparable to the reference standard GC376. Despite the structural similarity between the three compounds, only 1 showed a promising effect. The mechanism of inhibition is discussed in light of a series of extensive molecular docking, classical and steered molecular dynamics simulation experiments. This paper sheds light on indole diketopiperazine alkaloids as a potential structural motif against SARS-CoV-2 Mpro. Additionally, it highlights the potential of different molecular docking and molecular dynamics simulation approaches in the discrimination between active and inactive structurally related Mpro inhibitors.

Highlights

We report the discovery of a previously reported indole diketopiperazine alkaloid neoechinulin A (1), as a promising SARS-CoV-2 main protease (Mpro) inhibitor through bioguided screening
Extraction, and fractionation with organic solvents with different polarities followed by SARS-CoV-2 Mpro screening, indicated the dichloromethane (DCM)
HSQC spectra using SMART 2.1 database [19] and The Natural Products Atlas 2.0 [20], in addition to comparison with the literature data. This analysis led to the identification of the isolated metabolites as two prenylated indole diketopiperazines (DKP) neoechinulin

Summary

Introduction

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has cost many lives and put the world economy on hold in 2020, with extreme consequences. In December 2021, the number of confirmed SARS-CoV-2 cases worldwide reached around 350 million, with more than. 5.5 million reported deaths [1]. The world’s focus suddenly shifted to the scientific community, which has diligently delivered several vaccines that positively impacted the new cases and hospitalization. Apparent imbalances in the world economy are causing a delay in the rolling out of the vaccines, especially in low-income countries, delaying the

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