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

Thomas Scior¹, Hans-Georg Mack², José Antonio Guevara García³, Wolfhard Koch⁴

¹Departamento de Farmacia. Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Colonia San Manuel, Puebla, Mexico; ²Institut für Physikalische Chemie, Universität Tübingen, Tübingen, Germany; ³Laboratorio de Investigación en Bioinorgánica y Biorremediación (LIByB). Departamento de Ciencias Básicas, Ingeniería y Tecnología, Universidad Autónoma de Tlaxcala, Apizaco, Tlaxcala, Mexico; ⁴Facultad de Estudios Superiores Zaragoza (FESZ), Universidad Nacional Autónoma de México (UNAM), Colonia Ejército de Oriente, Delegación Iztapalapa, Mexico City, Mexico

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: vanadium compounds, diabetes mellitus, molecular modeling, computational quantum chemistry, PTP-1B