Interaction of copper potential metallodrugs with TMPRSS2: A comparative study of docking tools and its implications on COVID-19

Abstract

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. For the virus to enter the host cell, its spike (S) protein binds to the ACE2 receptor, and the transmembrane protease serine 2 (TMPRSS2) cleaves the binding for the fusion. As part of the research on COVID-19 treatments, several Casiopeina-analogs presented here were looked at as TMPRSS2 inhibitors. Using the DFT and conceptual-DFT methods, it was found that the global reactivity indices of the optimized molecular structures of the inhibitors could be used to predict their pharmacological activity. In addition, molecular docking programs (AutoDock4, Molegro Virtual Docker, and GOLD) were used to find the best potential inhibitors by looking at how they interact with key amino acid residues (His296, Asp 345, and Ser441) in the catalytic triad. The results show that in many cases, at least one of the amino acids in the triad is involved in the interaction. In the best cases, Asp435 interacts with the terminal nitrogen atoms of the side chains in a similar way to inhibitors such as nafamostat, camostat, and gabexate. Since the copper compounds localize just above the catalytic triad, they could stop substrates from getting into it. The binding energies are in the range of other synthetic drugs already on the market. Because serine protease could be an excellent target to stop the virus from getting inside the cell, the analyzed complexes are an excellent place to start looking for new drugs to treat COVID-19.

Keywords: COVID-19; Casiopeina analogs; Casiopeina-like metallodrugs; DFT; TMPRSS2; copper; molecular docking.

FIGURE 1

Representation of the TMPRSS2 protein (PDB code: 7MEQ) using Biovia/Discovery Studio v. 20.1. On the right side is the active site of the protein, where the triad of amino acids is located (His296, Asp345, Ser441).

FIGURE 2

Optimized molecular structures of the copper complexes calculated with the mPW1PW91 functional in an aqueous solution.

FIGURE 3

(A) Reactivity global indices $\chi$ ; $\eta$ , $\omega$ , and E_gap; and (B) Reactivity global index $s$ of the copper complexes calculated with the mPW1PW91 functional in an aqueous solution.

FIGURE 4

Binding interactions between [Cu(Bipy)(Lys)(H₂O)]²⁺ and the protein (7MEQ).

FIGURE 5

The re-docking result of the structure 7MEQ. MVD generated an RMSD of 0.58 Å. The pose structure of the nafamostat is indicated in red, whereas the inhibitor’s crystallographic coordinates are light gray—an image generated by the MVD program.

FIGURE 6

Docking results for the compounds [Cu(Bipy)(Arg)(H₂O)]²⁺ (red) and nafamostat (light gray).

FIGURE 7

Intermolecular hydrogen bonds (dashed blue lines) between the [Cu(Bipy)(Arg)(H₂O)]²⁺ compound and the protein.

FIGURE 8

Representations 3D and 2D of the [Cu(Bipy)(Orn)(H₂O)]²⁺ (A) and [Cu(Bipy)(Orn)]²⁺ (B) with 7MEQ.