Cheminformatics approach to identify andrographolide derivatives as dual inhibitors of methyltransferases (nsp14 and nsp16) of SARS-CoV-2

Abstract

The Covid-19 pandemic outbreak has accelerated tremendous efforts to discover a therapeutic strategy that targets severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to control viral infection. Various viral proteins have been identified as potential drug targets, however, to date, no specific therapeutic cure is available against the SARS-CoV-2. To address this issue, the present work reports a systematic cheminformatic approach to identify the potent andrographolide derivatives that can target methyltransferases of SARS-CoV-2, i.e. nsp14 and nsp16 which are crucial for the replication of the virus and host immune evasion. A consensus of cheminformatics methodologies including virtual screening, molecular docking, ADMET profiling, molecular dynamics simulations, free-energy landscape analysis, molecular mechanics generalized born surface area (MM-GBSA), and density functional theory (DFT) was utilized. Our study reveals two new andrographolide derivatives (PubChem CID: 2734589 and 138968421) as natural bioactive molecules that can form stable complexes with both proteins via hydrophobic interactions, hydrogen bonds and electrostatic interactions. The toxicity analysis predicts class four toxicity for both compounds with LD₅₀ value in the range of 500-700 mg/kg. MD simulation reveals the stable formation of the complex for both the compounds and their average trajectory values were found to be lower than the control inhibitor and protein alone. MMGBSA analysis corroborates the MD simulation result and showed the lowest energy for the compounds 2734589 and 138968421. The DFT and MEP analysis also predicts the better reactivity and stability of both the hit compounds. Overall, both andrographolide derivatives exhibit good potential as potent inhibitors for both nsp14 and nsp16 proteins, however, in-vitro and in vivo assessment would be required to prove their efficacy and safety in clinical settings. Moreover, the drug discovery strategy aiming at the dual target approach might serve as a useful model for inventing novel drug molecules for various other diseases.

Keywords: Andrographolide; Covid-19; Drug discovery; Natural compounds; nsp14; nsp16.

Figure 1

3D illustration of the superimposed (a) SAH and (b) SFG at the active site of nsp14 and nsp16 protein respectively. Color code: co-crystal SAH/SFG (red) and re-docked SAH/SFG (blue).

Figure 2

The molecular interactions between the hit compounds and the nsp14 protein with 3D (left panel, a→e) and 2D (right panel, a’→e’) representations. The protein structure is represented in the tan color and the compounds are depicted with stick models; (a,a’) SAH, (b,b’) 44437487, (c,c’) 44437491, (d,d’) 2734589 and (e,e’) 138968421.

Figure 3

The molecular interactions between the hit compounds and the nsp16 protein with 3D (left panel, a→e) and 2D (right panel, a’→e’) representations. The protein structure is represented in the tan color and the compounds are depicted with stick models; (a,a’) SFG, (b,b’) 44437487, (c,c’) 44437491, (d,d’) 2734589 and (e,e’) 138968421.

Figure 4

Comparison of molecular dynamics simulations analysis of the hit compounds and control complexed with nsp14 protein during a 300 ns simulation period; (a) RMSD, (b) hydrogen bond formations, (c) radius of gyration (Rg), (d) solvent accessible surface area (SASA), and (e) RMSF plot.

Figure 5

Comparison of molecular dynamics simulations analysis of the hit compounds and controls with nsp16 protein during a 300 ns simulation period; (a) RMSD, (b) hydrogen bond formations, (c) radius of gyration (Rg), (d) solvent accessible surface area (SASA), (e) RMSF plot.

Figure 6

Spatial shifting of the compounds from the binding pocket of the nsp14 (left) and nsp16 (right) protein showing initial (blue colour) and final (red colour) conformation of (a,a’) SAH, (b,b’) 44437487, (c,c’) 44437491, (d,d’) 2734589 and (e,e’) 138968421.

Figure 7

Plot depicting calculated binding free energies of the hit compounds and SAH/SFG with nsp14 and nsp16 protein by MM-GBSA calculation. (SAH = co-crystal of nsp14 and SFG = co-crystal of nsp16).

Figure 8

Plot depicting the hot residues in the binding pocket of (a) nsp14 and (b) nsp16 protein upon interaction with control SAH/SFG, 44437487, 44437491, 2734589 and 138968421.

Figure 9

3D depiction of frontier molecular orbitals (FMOs) with band gap energy for the compounds (a) SAH (b) SFG (c) 44437487, (d) 44437491, (e) 2734589 and (f) 138968421.

Figure 10

Molecular electronic potential (MEP) maps for the compounds (a) SAH (b) SFG (c) 44437487 (d) 44437491 (e) 2734589 and (f) 138968421.