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Publication
QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity
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Advisor(s)
Abstract(s)
Multidrug resistance (MDR) represents a major limitation for cancer chemotherapy. There are several
mechanisms of MDR but the most important is associated with P-glycoprotein (P-gp) overexpression.
The development of modulators of P-gp that are able to re-establish drug sensitivity of resistant cells
has been considered a promising approach for overcoming MDR. Macrocyclic lathyrane and jatro phane-type diterpenes from Euphorbia species were found to be strong MDR reversing agents. In this
study we applied quantitative structure–activity relationship (QSAR) methodology in order to identify
the most relevant molecular features of macrocyclic diterpenes with P-gp inhibitory activity and to deter mine which structural modifications can be performed to improve their activity. Using experimental bio logical data at two concentrations (4 and 40 lg/ml), we developed a QSAR model for a set of 51 bioactive
diterpenic compounds which includes lathyrane and jatrophane-type diterpenes and another model just
for jatrophanes. The cross-validation correlation values for all diterpenes QSAR models developed for bio logical activities at compound concentrations of 4 and 40 lg/ml were 0.758 and 0.729, respectively.
Regarding the prediction ability, we get R2
pred values of 0.765 and 0.534 for biological activities at com pound concentrations of 4 and 40 lg/ml, respectively. Applying the cross-validation test to jatrophanes
QSAR models, we obtained 0.680 and 0.787 for biological activities at compound concentrations of 4 and
40 lg/ml concentrations, respectively. For the same concentrations, the obtained R2
pred values for jatro phanes models were 0.541 and 0.534, respectively. The obtained models were statistically valid and
showed high prediction ability.
Description
Keywords
Quantitative structure–activity relationship P-glycoprotein Macrocyclic diterpenes Multidrug resistance Multiple linear regression . Faculdade de Ciências Exatas e da Engenharia
Citation
Sousa, I. J., Ferreira, M. J. U., Molnár, J., & Fernandes, M. X. (2013). QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity. European Journal of Pharmaceutical Sciences, 48(3), 542-553.
Publisher
Elsevier