Abstract
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 0.875, R pred 0.921) and human colon adenocarcinoma (q 0.820, R 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.
Original language | English |
---|---|
Pages (from-to) | 629-645 |
Number of pages | 17 |
Journal | Future Medicinal Chemistry |
Volume | 8 |
Issue number | 6 |
DOIs | |
Publication status | Published - Apr 2016 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2016 Future Science Ltd.
Keywords
- P-gp
- efflux modulation
- macrocyclic diterpenes
- multidrug resistance
- pharmacophores
- structure-activity relationships
- virtual screening