Optimizing the macrocyclic diterpenic core toward the reversal of multidrug resistance in cancer

From a dataset obtained by chemical derivatization of a macrocyclic diterpenic scaffold, in silico approaches identified which structural features correlate with experimental modulation of P-gp activity. Results/methodology: Ninety-two percent of the strongest MDR modulators were positively identified within the dataset by virtual screening. Quantitative structure-activity relationships models with high robustness and predictability were obtained for both MDR1-transfected L5178Y mouse lymphoma T-cells (q(2) 0.875, R(2) pred 0.921) and human colon adenocarcinoma (q(2) 0.820, R(2) pred 0.951) cell lines. A new pharmacophoric model suggests that charge distribution within the molecule is important for biological activity. For the studied diterpenes, the conformation of the macrocyclic scaffold and its substitution pattern are the main determinants for the biological activity, being related with steric and electrostatic factors.