Antidiabetic Bis-Maltolato-OxoVanadium(IV): conversion of inactive trans- to bioactive cis-BMOV for possible binding to target PTP-1B

Abstract

The postulated transition of Bis-Maltolato-OxoVanadium(IV) (BMOV) from its inactive trans- into its cis-aquo-BMOV isomeric form in solution was simulated by means of computational molecular modeling. The rotational barrier was calculated with DFT - B3LYP under a stepwise optimization protocol with STO-3G, 3-21G, 3-21G*, and 6-31G ab initio basis sets. Our computed results are consistent with reports on the putative molecular mechanism of BMOV triggering the insulin-like cellular response (insulin mimetic) as a potent inhibitor of the protein tyrosine phosphatase-1B (PTP-1B). Initially, trans-BMOV is present in its solid dosage form but in aqueous solution, and during oral administration, it is readily converted into a mixture of "open-type" and "closed-type" complexes of cis-aquo-BMOV under equilibrium conditions. However, in the same measure as the "closed-type" complex binds to the cytosolic PTP-1B, it disappears from solution, and the equilibrium shifts towards the "closed-type" species. In full accordance, the computed binding mode of cis-BMOV is energetically favored over sterically hindered trans-BMOV. In view of our earlier report on prodrug hypothesis of vanadium organic compounds the present results suggest that cis-BMOV is the bioactive species.

Keywords: PTP-1B; computational quantum chemistry; diabetes mellitus; molecular modeling; vanadium compounds.

Figure 1

Structural representation of both isomers of BMOV in solution: (left) trans-BMOV, (right) the cis-acuo species where a solvent water moiety is attached to the central metal atom in the place of the electron lone pair. Despite the formal change in coordination geometries (trigonal bipyramidal to octahedral) due to the change of ligand number from 5 to 6 the over-all structure remains unchanged.

Figure 2

Structural display of reference crystal structure of protein tyrosine phosphatase1B (PDB code: 2hnq). Tungstate, a tetraoxo homologue to vanadate, is bound to the active site (see text). Except for a few labeled amino acids the protein is represented by its backbone with helical parts in red, turns and loops in white, and beta strands in light blue color.

Figure 3

Result of the computed binding mode of the “closed-type cis-aquo-BMOV” complex at the active site (stick representation of 3D-model). Element color code: white C, light blue H, red O, dark blue N, yellow S or V, magenta LP.

Figure 4

Results of the full optimization for the trans-BMOV complex: (Top left) Tabular listing of total energies (in Hartree) for different basis sets. The asterisk marks a local energy value. (Plot below) Total energy variation graphics (in Hartree): black: without solvent; red: with solvent; blue: interaction model with a PCM-type solvent. (Right side) Schematic plot of the optimized structure.

Figure 5

Results of the full optimization for the “closed-type cis-aquo-BMOV” complex: (Top left) Total energies (in Hartree) listed for different basis sets. The asterisk marks a local energy value. (Plot below) Total energy variation graphics (in Hartree): indigo blue: without solvent; green: interaction model with a dipolar solvent; blue: interaction model with a PCM-type solvent. (Right side) Schematic plot of the optimized structure.

Figure 6

Results of the full optimization for the “open-type cis-aquo-BMOV” complex: (Top left) Total energies (in Hartree) for the basis set 6-31G. (Plot below) Total energy bar graphics (in Hartree): blue: without solvent; red: interaction model with a dipolar solvent; yellow: interaction model with a PCM-type solvent. (Right side) Schematic plot of the optimized structure.

Figure 7

Energy diagram of the computed cis-trans conversion mechanism for the bioactive BMOV in its “closed-type cis-aquo”-form. In aqueous solution, the administered compound, trans-BMOV, intermediately converts into the “open-type cis-aquo-BMOV” complex being in equilibrium with the “closed-type cis-aquo-BMOV”. Note, the activated transition complex of the reaction trans-BMOV + H₂O remains hitherto unknown. NIR, normal insulin response; IR, state of insulin resistance.

Figure 8

Schematic viewing of our elaborated pharmacophore model with the active site of PTP-1B: binding- relevant amino acids are labeled according to the numbering scheme found in PDB entry: 2hnq. Not shown: upon blocking the enzyme PTP-1B, the insulin docked to its extracellular membrane receptor triggers the intercellular signal and the cell responds with normal glucose up-take. Boxed amino acids are not structurally depicted just labeled by their code for figure clarity.