TY - JOUR
T1 - Optimizing the macrocyclic diterpenic core toward the reversal of multidrug resistance in cancer
AU - Baptista, Rafael
AU - Ferreira, Ricardo J.
AU - Dos Santos, Daniel Jva
AU - Fernandes, Miguel X.
AU - Ferreira, Maria-José U.
PY - 2016/4/22
Y1 - 2016/4/22
N2 - 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.
AB - 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.
KW - ATP-Binding Cassette, Sub-Family B, Member 1
KW - Animals
KW - Antineoplastic Agents, Phytogenic
KW - Cell Line, Tumor
KW - Diterpenes
KW - Drug Resistance, Multiple
KW - Drug Resistance, Neoplasm
KW - Drug Screening Assays, Antitumor
KW - Euphorbia
KW - Humans
KW - Macrocyclic Compounds
KW - Mice
KW - Molecular Conformation
KW - Quantitative Structure-Activity Relationship
KW - Journal Article
U2 - 10.4155/fmc.16.11
DO - 10.4155/fmc.16.11
M3 - Article
C2 - 27105294
SN - 1756-8919
VL - 8
SP - 629
EP - 645
JO - Future Medicinal Chemistry
JF - Future Medicinal Chemistry
IS - 6
ER -
