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

Abstract

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.

Synthesis and Conjoint Experimental-DFT Characterization of Some Pyrazolone Functionalized Dioxovanadium (V) Schiff Base Complexes

“…35 The mass spectral data shows close agreement with the supposed molecular structure of the complex (4).…”

“…Density-functional theory (DFT) is a powerful method for predicting the geometry of vanadium compounds including large molecules [31][32][33][34][35][36][37]. The application of theoretical force constants to attain Cartesian representation is useful for the assumption of molecular symmetry.…”

Chimeric design, synthesis, and biological assays of a new nonpeptide insulin-mimetic vanadium compound to inhibit protein tyrosine phosphatase 1B

“…In the present work, due to the reported identification of a biomolecular target we could devise a so-called de novo design procedure. In a previous work, 35 we demonstrated that vanadium compounds stated in the literature as the most active antidiabetics are also potential PTP1B inhibitors. 35 Particularly, in the case of bis(maltolate) oxo-vanadium(IV) (BMOV) and ammonium bis(picolinate) oxo-vanadium(V), we determined the active conformations during simulated docking into the target enzyme (PTP1B).…”

“…31 Recently, literature evidence appears in support of the hypothesis that active vanadium compounds may have intrinsic affinity to the PTP1B catalytic site. [32][33][34][35] The insulin-like properties of vanadium have been demonstrated in a conclusive way based on in vitro experiments, 36 in vivo assays in rats 37,38 or mice, 39 as well as in patients with diabetes. 40 It is noteworthy to state that as yet all clinical studies have been carried out successfully using inorganic salts of vanadium, albeit it is beyond doubt that the true potential lies in the use of organic vanadium complexes, judging from the higher activity and the lower toxicity rates.…”

Synthesis and Conjoint Experimental - DFT Characterization of some Pyrazolone Functionalized Dioxovanadium (V) Schiff Base Complexes

“…Density-functional theory (DFT) is a powerful method for predicting the geometry of vanadium compounds [31][32][33][34][35][36] including large molecules [37]. The application of theoretical force constants to attain Cartesian representation is useful for the assumption of molecular symmetry.…”