Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations

Abstract

This paper proposes natural drug candidate compounds for the treatment of coronavirus disease 2019 (COVID-19). We investigated the binding properties between the compounds in the Moringa oleifera plant and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 using molecular docking and ab initio fragment molecular orbital calculations. Among the 12 compounds, niaziminin was found to bind the strongest to Mpro. We furthermore proposed novel compounds based on niaziminin and investigated their binding properties to Mpro. The results reveal that the introduction of a hydroxyl group into niaziminin enhances its binding affinity to Mpro. These niaziminin derivatives can be promising candidate drugs for the treatment of COVID-19.

Keywords: COVID-19; Fragment molecular orbital; In silico drug design; Main protease; Molecular docking; Molecular simulation; Moringa oleifera; Natural product; SARS-CoV-2.

Graphical abstract

Fig. 1

The chemical structures of the 12 compounds found in Moringa oleifera.

Fig. 2

Structure of Mpro and its ligand-binding pocket marked by a yellow ellipse. Charge distribution on Mpro is shown in red (negative), blue (positive), and green (neutral), respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

The inter fragment interaction energies (IFIEs) between compound 9 and each Mpro residue for the structures of (a) cluster 1, (b) cluster 3, and (c) cluster 6. The total IFIEs between compound 9 and all Mpro residues are also shown for each cluster. The red bars indicate the residues with attractive IFIE, the size of which is larger than 10 kcal/mol. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

The interacting structures between compound 9 (ball-and-stick model) and selected important Mpro residues (stick model) in the optimized structure of the Mpro + compound 9 complex for cluster 6. (a) Compound 9 and Glu166, and (b) compound 9 and Asn142, Gly143, Cys145, and Glu189. Hydrogen bonding and electrostatic interactions are indicated by red and blue lines, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

(a) The inter fragment interaction energies (IFIEs) between compound 12 and each Mpro residue for the structure of cluster 2. The total IFIE between compound 12 and all Mpro residues is also shown. The red bars indicate the residues with attractive IFIE, the size of which is larger than 10 kcal/mol. (b) The interacting structures between compound 12 (ball-and-stick model) and selected important Mpro residues (stick model) in the optimized structure of the Mpro + compound 12 complex for cluster 2. Hydrogen bonding, electrostatic, and NH-π interactions are indicated by red, blue, and orange lines, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

The inter fragment interaction energies (IFIEs) between our proposed compound 9 derivatives and the Mpro residues. The red bars indicate the residues with attractive IFIE, the size of which is larger than 10 kcal/mol. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

The difference in inter fragment interaction energies (IFIEs) between the Mpro residues and (a) compounds 9c and 9 and (b) compounds 9d and 9. The red bars indicate the residues with IFIE difference, the size of which is larger than 5 kcal/mol. These residues interact more strongly with compound 9c/9d compared with compound 9. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 8

The interacting structures between our proposed compounds (ball-and-stick model) and selected important Mpro residues (stick model): (a) compound 9, (b) compound 9c, and (c) compound 9d. The red and blue lines indicate hydrogen bonding and electrostatic interactions, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)