An Androsterone-H2 @C60 hybrid: Synthesis, Properties and Molecular Docking Simulations with SARS-Cov-2

Abstract

We report the synthesis and characterization of a fullerene-steroid hybrid that contains H₂ @C₆₀ and a dehydroepiandrosterone moiety synthesized by a cyclopropanation reaction with 76 % yield. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level predict the most stable conformation and that the saturation of a double bond is the main factor causing the upfield shielding of the signal appearing at -3.13 ppm, which corresponds to the H₂ located inside the fullerene cage. Relevant stereoelectronic parameters were also investigated and reinforce the idea that electronic interactions must be considered to develop studies on chemical-biological interactions. A molecular docking simulation predicted that the binding energy values for the protease-hybrid complexes were -9.9 kcal/mol and -13.5 kcal/mol for PL^pro and 3CL^pro respectively, indicating the potential use of the synthesized steroid-H₂ @C₆₀ as anti-SARS-Cov-2 agent.

Keywords: SARS-Cov-2; cyclopropanation; fullerenes; molecular docking; steroid hybrids.

Scheme 1

Synthesis of hybrid steroid‐H₂@C₆₀. i) CBr₄, DBU, toluene, room temperature.

Figure 1

Minimum energy conformation of compounds 3 obtained by the DFT−D3(BJ) method at the PBE/6‐311G(d,p) level of theory Bond distances are given in Å and dihedral angle in degree °.

Figure 2

Non‐covalent interactions (NCI) analysis of compound 3 in the gas phase. Isosurfaces represent the regions of interactions where green represents weak van der Waals interactions, blue strong attractive interactions and red strong repulsive interactions. For a better visualization an arrow focuses on interactions near to the A‐ring (2b) and near to the D‐ring (2c) of the steroid scaffold.

Figure 3

Depiction of the molecular electrostatic potential maps for the optimized functionalized endohedral fullerene 3 (a) and H₂@C₆₀ (b). The red color, represented negative potential, blue color the positive potential and green color the uncharged regions.

Figure 4

Low‐energy binding conformations of 3 bound to human SARS‐Cov‐2 generated by molecular docking. The proteases are shown as an electrostatic surface model and the ligand is represented in sticks. The hydrogen molecule is represented in spheres. (A) Structure of PL^pro‐fullerene hybrid complex. (B) Structure of 3CL^pro‐fullerene hybrid complex.

Figure 5

Low‐energy binding conformations of 3 bound to human SARS‐Cov‐2 generated by molecular docking. The proteases are shown as an electrostatic surface model and the ligand is represented in sticks. The hydrogen molecule is represented in spheres. (A) Structure of PL^pro‐fullerene hybrid complex. (B) Structure of 3CL^pro‐fullerene hybrid complex.

Figure 6

Low‐energy binding conformations of 3 and H₂@C₆₀ bound to human SARS‐Cov‐2 enzymes generated by molecular docking. The proteases are shown in the cartoon model and the ligand is represented in sticks, H₂@C₆₀ in grey and 3 in yellow. The interacting residues (distance≤0.4 nm) are represented in sticks and the hydrogen molecule was represented in spheres. A) Superimposed image of the H₂@C₆₀−PL^pro and hybrid 3‐PL^pro complexes in the active site. (B) Superimposed image of the H₂@C₆₀−3CL^pro and hybrid 3–3CL^pro complexes in the active site.