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. 2022 May 11;28(6):144.
doi: 10.1007/s00894-022-05137-4.

Indole alkaloids as potential candidates against COVID-19: an in silico study

Mehran Mohseni  1 , Hamed Bahrami  2 , Bahman Farajmand  2 , Faezeh Sadat Hosseini  3 , Massoud Amanlou  3   4 , Hafezeh Salehabadi  5
Affiliations

Indole alkaloids as potential candidates against COVID-19: an in silico study

Mehran Mohseni et al. J Mol Model. .

Abstract

COVID-19 has recently grown to be pandemic all around the world. Therefore, efforts to find effective drugs for the treatment of COVID-19 are needed to improve humans' life quality and survival. Since the main protease (Mpro) of SARS-CoV-2 plays a crucial role in viral replication and transcription, the inhibition of this enzyme could be a promising and challenging therapeutic target to fight COVID-19. The present study aims to identify alkaloid compounds as new potential inhibitors for SARS-CoV-2 Mpro by the hybrid modeling analyses. The docking-based virtual screening method assessed a collection of alkaloids extracted from over 500 medicinal plants and sponges. In order to validate the docking process, classical molecular dynamic simulations were applied on selected ligands, and the calculation of binding free energy was performed. Based on the proper interactions with the active site of the SARS-CoV-2 Mpro, low binding energy, few side effects, and the availability in the medicinal market, two indole alkaloids were found to be potential lead compounds that may serve as therapeutic options to treat COVID-19. This study paves the way for developing natural alkaloids as stronger potent antiviral agents against the SARS-CoV-2.

Keywords: Docking; Indole alkaloids; MM-PBSA; Molecular dynamic simulations; SARS-CoV-2 main protease inhibitor; Virtual screening.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The overview diagram of therapeutic targets in SARS-CoV-2
Fig. 2
Fig. 2
Workflow of the methodology used for virtual screening, molecular dynamics, and MM-PBSA binding energy calculation of natural alkaloids to get a SARS-CoV-2 Mpro inhibitor
Fig. 3
Fig. 3
Residues involved in the interaction of a N3 and b PF-00835231 with SARS-CoV-2 Mpro according to the docking methodology
Fig. 4
Fig. 4
a 2D representation of nelfinavir interaction with SARS-CoV-2 Mpro active site. b Superimpose nelfinavir (slate) and remdesivir (orange) in the active site. c 2D representation of remdesivir interaction in the active site
Fig. 5
Fig. 5
Natural sources a Zizyphus jujuba [37], b Diplosoma virens [38], c Aster tataicusb [39], d Cliona celata [40], e Pausinystalia johimbe [41], f Catharanthus roseus [42]
Fig. 6
Fig. 6
a Superimpose of the yohimbine and ajmalicine with SARS-CoV-2 Mpro active site. Yohimbine and ajmalicine are presented in yellow and green, respectively. b, d 3D and 2D representation of yohimbine interaction; c, e 3D and 2D representation of ajmalicine interaction.
Fig. 7
Fig. 7
The RMSD plots as a function of simulation time. a Repeat simulations of free SARS-CoV-2 Mpro backbone, b repeat simulations of SARS-CoV-2 Mpro backbone in complex with ajmalicine, and c repeat simulations of SARS-CoV-2 Mpro backbone in complex with yohimbine
Fig. 8
Fig. 8
The RMSD plots as a function of simulation time. a Repeat simulations of ajmalicine, and b repeat simulations of yohimbine
Fig. 9
Fig. 9
The RMSF plots of ajmalicine and yohimbine-SARS-CoV-2 Mpro complexes from repeat simulations
Fig. 10
Fig. 10
The total binding energy contribution of amino acids of SARS-CoV-2 Mpro is involved in interaction with ajmalicine (blue) and yohimbine (red)
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