TY - JOUR
T1 - Toward a better pharmacophore description of P-glycoprotein modulators, based on macrocyclic diterpenes from euphorbia species
AU - Ferreira, Ricardo J.
AU - Dos Santos, Daniel J.V.A.
AU - Ferreira, Maria José U.
AU - Guedes, Rita C.
PY - 2011/6/27
Y1 - 2011/6/27
N2 - Multidrug resistance related to the increased expression of P-glycoprotein (P-gp) by cancer cells is the major contributor for the failure of chemotherapeutic treatments. Starting from pharmacophores and data already published and in macrocyclic diterpenes isolated from Euphorbia species, a comprehensive study of pharmacophore definitions of features was performed in order to obtain a new improved four-point pharmacophore able to detect literature and in-house modulators and simultaneously specific enough to avoid the detection of most nonactive molecules in a universe of 152 (literature), 74 (in-house), and 46 (inactive) molecules. This pharmacophore detects 84.2% of the molecules described in the literature, along with 100% detection of in-house isolated compounds and 19.5% of false positives. The importance of the hydrophobic and electron acceptor moieties as essential features for recognition of different molecules by the P-gp drug-binding site is clarified. The best combination of acceptor, donor, hydrophobic, and aromatic characteristics that contribute for the increased selectivity shown by the described pharmacophore is evaluated, and the protonation state of the molecules is also addressed.
AB - Multidrug resistance related to the increased expression of P-glycoprotein (P-gp) by cancer cells is the major contributor for the failure of chemotherapeutic treatments. Starting from pharmacophores and data already published and in macrocyclic diterpenes isolated from Euphorbia species, a comprehensive study of pharmacophore definitions of features was performed in order to obtain a new improved four-point pharmacophore able to detect literature and in-house modulators and simultaneously specific enough to avoid the detection of most nonactive molecules in a universe of 152 (literature), 74 (in-house), and 46 (inactive) molecules. This pharmacophore detects 84.2% of the molecules described in the literature, along with 100% detection of in-house isolated compounds and 19.5% of false positives. The importance of the hydrophobic and electron acceptor moieties as essential features for recognition of different molecules by the P-gp drug-binding site is clarified. The best combination of acceptor, donor, hydrophobic, and aromatic characteristics that contribute for the increased selectivity shown by the described pharmacophore is evaluated, and the protonation state of the molecules is also addressed.
UR - http://www.scopus.com/inward/record.url?scp=79959764016&partnerID=8YFLogxK
U2 - 10.1021/ci200145p
DO - 10.1021/ci200145p
M3 - Article
C2 - 21604687
AN - SCOPUS:79959764016
SN - 1549-9596
VL - 51
SP - 1315
EP - 1324
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 6
ER -