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. 2021 Mar 7;13(5):6258-6272.
doi: 10.18632/aging.202703. Epub 2021 Mar 7.

Screening potential FDA-approved inhibitors of the SARS-CoV-2 major protease 3CLpro through high-throughput virtual screening and molecular dynamics simulation

Wen-Shan Liu  1 , Han-Gao Li  1 , Chuan-Hua Ding  1 , Hai-Xia Zhang  1 , Rui-Rui Wang  2 , Jia-Qiu Li  3
Affiliations

Screening potential FDA-approved inhibitors of the SARS-CoV-2 major protease 3CLpro through high-throughput virtual screening and molecular dynamics simulation

Wen-Shan Liu et al. Aging (Albany NY). .

Abstract

It has been confirmed that the new coronavirus SARS-CoV-2 caused the global pandemic of coronavirus disease 2019 (COVID-19). Studies have found that 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for virus replication, and could be used as a potential target to inhibit SARS-CoV-2. In this work, 3CLpro was used as the target to complete the high-throughput virtual screening of the FDA-approved drugs, and Indinavir and other 10 drugs with high docking scores for 3CLpro were obtained. Studies on the binding pattern of 3CLpro and Indinavir found that Indinavir could form the stable hydrogen bond (H-bond) interactions with the catalytic dyad residues His41-Cys145. Binding free energy study found that Indinavir had high binding affinity with 3CLpro. Subsequently, molecular dynamics simulations were performed on the 3CLpro and 3CLpro-Indinavir systems, respectively. The post-dynamic analyses showed that the conformational state of the 3CLpro-Indinavir system transformed significantly and the system tended to be more stable. Moreover, analyses of the residue interaction network (RIN) and H-bond occupancy revealed that the residue-residue interaction at the catalytic site of 3CLpro was significantly enhanced after binding with Indinavir, which in turn inactivated the protein. In short, through this research, we hope to provide more valuable clues against COVID-19.

Keywords: COVID-19; Indinavir; SARS-CoV-2; molecular docking; molecular dynamics simulation.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
The complex structure of 3CLpro protein and synthetic peptidomimetic inhibitor N3. 3CLpro contains three domains, namely domain I, domain II, and domain III, and a connecting loop. Residues His41 and Cys145 are important catalytic dyads.
Figure 2
Figure 2
Investigation on the binding pattern of 3CLpro and Indinavir. (A) The location of the binding pocket between 3CLpro and Indinavir. (B) The enlarged view of the binding pocket of 3CLpro and Indinavir. (C) The interaction 2D diagram between 3CLpro and Indinavir. The green rectangles represent VDW interaction. The pink rectangles represent charge and H-bond interactions. Here, the H-bond interactions with the main residues are indicated by the green dashed arrow pointing to the electron donor, and the H-bond interactions with the side chain residues are indicated by the blue dashed arrow pointing to the electron donor.
Figure 3
Figure 3
The first 10 main residues in 3CLpro that contribute to the binding free energy of 3CLpro and Indinavir. The ordinate indicates the value of binding free energy, and the abscissa indicates the residue.
Figure 4
Figure 4
Stability evaluation of 3CLpro system and 3CLpro-Indinavir system. (A) RMSD of all main chain atoms of 3CLpro system and 3CLpro-Indinavir system. (B) RMSF of side chain atoms of 3CLpro system and 3CLpro-Indinavir system. The black line indicates the result of the 3CLpro system, and the red line indicates the result of the 3CLpro-Indinavir system. In addition, these regions (residues Glu47-Tyr54, Phe140-Cys145, His163-Pro168 and Val186-Thr190) are highlighted with blue dotted box.
Figure 5
Figure 5
The variance contribution of the principal components and the PCA scatter plots generated along the projection of the first two eigenvectors (PC1 and PC2) in the space of the 3CLpro (A) and 3CLpro-Indinavir (B) systems, respectively.
Figure 6
Figure 6
DCCM analysis of Cα atoms for 3CLpro system (A) and 3CLpro-Indinavir system (B), respectively. The red regions indicate negative correlation, and the blue regions indicate positive correlation. The darker the color, the stronger the correlation. Regions with significant differences in correlated motions have been marked with black dashed boxes.
Figure 7
Figure 7
The RINs results of the residues-residues around the catalytic dyads His41-Cys145 of the 3CLpro system and the 3CLpro-Indinavir system, respectively. Among them, the red line represents the H-bond interaction, the black line represents the VDW interaction, and the green line represents the Pi-Pi interaction.
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