Background: 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.
Conclusion: 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.
Keywords: P-gp; efflux modulation; macrocyclic diterpenes; multidrug resistance; pharmacophores; structure–activity relationships; virtual screening.