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.
|Number of pages||17|
|Journal||Future Medicinal Chemistry|
|Publication status||Published - 22 Apr 2016|
- ATP-Binding Cassette, Sub-Family B, Member 1
- Antineoplastic Agents, Phytogenic
- Cell Line, Tumor
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Drug Screening Assays, Antitumor
- Macrocyclic Compounds
- Molecular Conformation
- Quantitative Structure-Activity Relationship
- Journal Article