title: 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.
authors.affiliation: Departamento de Farmacia, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Colonia San Manuel, Puebla, Mexico. tscior@siu.buap.mx
authors.forename: Thomas
authors.initials: T
authors.lastname: Scior
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Mack
authors.forename: José Antonio Guevara
authors.initials: JA
authors.lastname: García
authors.forename: Wolfhard
authors.initials: W
authors.lastname: Koch