Molecular modeling of indazole-3-carboxylic acid and its metal complexes (Zn, Ni, Co, Fe and Mn) as NO synthase inhibitors: DFT calculations, docking studies and molecular dynamics simulations

• HL and their M-complexes were investigated by means of molecular modelling. • The M-OH 2 bond obtained showed good agreement with biological activity. • M-ONO - interaction is more effective than the M-H 2 O the more active the complex is. • Docking and MD showed that HL bind to Fe-center and M-complexes bind to residues. • Inhibitors makes the exit of cofactor HB4 from active site slower. A set of density function theory (DFT) calculations, docking and molecular dynamics (MD) simulations were used to study (theoretically) the inhibition of the enzyme nitric oxide (NO) synthase by indazole-3-carboxylic acid (HL) and its metal complexes with Zn, Ni, Co, Fe, and Mn. DFT provided the geometries and electronic structures of each compound and showed that the M-OH 2 bond becomes weaker the higher the biological activity, in addition to proving that the M-ONO - interaction is more effective than the M-H 2 O the more active the complex is. Docking studies provided the best binding modes of each inhibitor to the enzyme, and MD simulations proved that the inhibitors remained at the docking region over the simulation. RMSD results indicated that the presence of the inhibitors made the affinity between cofactor tetrahydrobiopterin (HB4) and the binding site of heme group, greater. Therefore, DFT, docking and MD calculations suggest that, while HL should have high affinity by the substrate binding site, the metal complexes should have a favorable binding of the metal to the NO 2 – derivative.