Binding of pinoresinol derivatives to P-glycoprotein. A computational Study

GANCEDO, S.N.; LANZA-CASTRONUOVO, P.A.; JARA, G.E.; GONZÁLEZ M.L.; CARPINELLA M. C.; VERA D.M.A.

Congreso; 13th Latin American Conference on Physical Organic Chemistry; 2015

Multidrug resistance (MDR) is one of the major cause of failure of chemotherapy. The MDR mechanism of major clinical importance is the overexpression of the membrane pump P-glycoprotein (P-gp) which is capable of transporting various chemotherapeutic agents to the outside of the tumor cell, thus preventing them to reach the intracellular concentration needed to be effective. [1] This fact has prompted the interest of many researchers to develop P-gp inhibitors as a way for reverting MDR in human cancers. Plants result an invaluable source of metabolites which present multiple chemical structures. Compounds from native and naturalized plants of central Argentina were tested for its capacity of reversing chemotherapic efflux by permorming MTT assay and the measurement of doxorubicin intacellular accumulation by flow cytometry, the compound (+)-pinorresinol obtained from ethanolic extract of Melia azedarach [2] showed no significant differences with respect to verapamil used as reference compound. Different related derivatives were tested in silico in order to obtain promising structures with improved activity. In this aim, compounds on Fig. 1 were docked in three different structural models of the P-gp including the experimental structure of the Mus musculus P-gp and a homology model of the H. sapiens protein, previously contributed. [2] The docking results for the proposed compounds were compared to those corresponding to verapamil and tariquidar, [2] as references of a first generation inhibitor a and a very powerful one (EC50 of 16.3 nM), respectively.For the compound having R1=R2=OMe, R3=H, a remarkable improvement over the isolated natural product was obtained, with an estimated Ki about 15 times smaller, it being between verapamil and tariquidar. The two most promising compounds were subject of contact analysis and short MD simulations in order to compare dynamical aspects of their binding modes compared to the reference inhibitors.