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; Bathini Thissera; Raha Orfali; Suzan E Jiffri; Mohammed Yaseen; Ahmed M Sayed; Mostafa E Rateb

doi:10.3390/md20030163

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

Mar Drugs. 2022 Feb 24;20(3):163. doi: 10.3390/md20030163.

Authors

Hani A Alhadrami^{1

2

3}, Gaia Burgio⁴, Bathini Thissera⁴, Raha Orfali⁵, Suzan E Jiffri⁶, Mohammed Yaseen⁴, Ahmed M Sayed⁷, Mostafa E Rateb⁴

Affiliations

¹ Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80402, Jeddah 21589, Saudi Arabia.
² Molecular Diagnostic Laboratory, King Abdulaziz University Hospital, King Abdulaziz University, P.O. Box 80402, Jeddah 21589, Saudi Arabia.
³ Special Infectious Agent Unit, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80402, Jeddah 21589, Saudi Arabia.
⁴ School of Computing, Engineering and Physical Sciences, University of the West of Scotland, Paisley PA1 2BE, UK.
⁵ Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia.
⁶ King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80402, Jeddah 21589, Saudi Arabia.
⁷ Department of Pharmacognosy, Faculty of Pharmacy, Nahda University, Beni-Suef 62513, Egypt.

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 M^pro 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 M^pro. Additionally, it highlights the potential of different molecular docking and molecular dynamics simulation approaches in the discrimination between active and inactive structurally related M^pro inhibitors.

Keywords: Aspergillus fumigatus; SARS-CoV-2 Mpro; molecular docking; neoechinulin A; steered molecular dynamics simulation.

MeSH terms

Alkaloids / chemistry
Alkaloids / isolation & purification
Antiviral Agents / chemistry*
Antiviral Agents / isolation & purification
Aspergillus fumigatus / chemistry
Coronavirus 3C Proteases / antagonists & inhibitors*
Cysteine Proteinase Inhibitors / chemistry*
Cysteine Proteinase Inhibitors / isolation & purification
Indole Alkaloids / chemistry*
Indole Alkaloids / isolation & purification
Molecular Docking Simulation
Molecular Dynamics Simulation
Piperazines / chemistry*
Piperazines / isolation & purification
SARS-CoV-2 / enzymology*

Substances

Alkaloids
Antiviral Agents
Cysteine Proteinase Inhibitors
Indole Alkaloids
Piperazines
eurocristatine
neoechinulin A
echinuline
Coronavirus 3C Proteases