Are vanadium complexes druggable against the main protease m ^pro of sars-cov-2? – a computational approach

Graphical abstract

Abstract

In silico techniques helped explore the binding capacities of the SARS-CoV-2 main protease (M ^pro) for a series of metalloorganic compounds. Along with small size vanadium complexes a vanadium-containing derivative of the peptide-like inhibitor N3 (N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-N1-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl] methyl }but-2-enyl)-l-leucinamide) was designed from the crystal structure with PDB entry code 6LU7. On theoretical grounds our consensus docking studies evaluated the binding affinities at the hitherto known binding site of M ^pro for binding vanadium complexes. The site is an evolutionarily fold unit which is structurally conserved among proteins belonging to the same enzyme class (EC 3). The highly conserved sequence of the SARS-CoV-2 protease M ^pro has a Cys-His dyad at the catalytic site that are characteristic of metal-dependent or metal-inhibited hydrolases. Therefore, M ^pro was superimposed to the human protein-tyrosine phosphatase 1B (hPTP1B) which is a key regulator at an early stage in the signalling cascade of the insulin hormone for glucose uptake into cells. Comparatively, the vanadium-ligand binding site of hPTP1B is located in a larger groove on the surface of M ^pro. Vanadium constitutes a well-known phosphate analogue. Hence, its study offers possibilities to design promising vanadium-containing binders to SARS-CoV-2. Given the favourable physicochemical properties of vanadium nuclei, such organic vanadium complexes could become drugs not only for pharmacotherapy but also diagnostic tools for early infection detection in patients. This work presents the in silico design of a potential lead vanadium compound. It was tested along with 20 other vanadium-containing complexes from the literature in a virtual screening test by docking against the inhibition of M ^pro of SARS-CoV-2.