Theoretical studies on 1,4-dihydropyridine derivatives as P-glycoprotein allosteric inhibitors: insights on symmetry and stereochemistry.

P-glycoprotein (P-gp) is a key efflux pump involved in cellular multidrug resistance (MDR), lowering the concentration of many anticancer drugs in tumor cells by pumping them into the extracellular milieu. While previous studies identified 1,4-dihydropyridines (DHP) as putative P-gp allosteric inhibitors, none reported the effect of stereochemistry on the ability of DHPs to bind P-gp. In the present study both symmetric (1) and asymmetric (2 R,S) DHPs were designed as P-gp inhibitors and, after biological evaluation, molecular docking and molecular dynamics simulation (MD) studies were performed to gain insights on how both scaffolds interact with P-gp. The results were thoroughly analyzed i) to evaluate the role of the different substituents and ii) to assess how stereochemistry may affect binding of DHPs to P-gp. Our results suggest that both the substitution pattern and stereochemistry may have a significant impact not only in drug binding but also on membrane permeation/accumulation, thus compromising in which site the DHPs may exert their effect as P-gp efflux inhibitors. Therefore, it is our conclusion that the stereochemistry cannot be neglected during the development of novel 1,4-dihydropyridine derivatives.Communicated by Ramaswamy H. Sarma.