TY - JOUR
T1 - Insights on P-glycoproteins efflux mechanism obtained by molecular dynamics simulations
AU - Ferreira, Ricardo J.
AU - Ferreira, Maria José U.
AU - Dos Santos, Daniel J.V.A.
PY - 2012/6/12
Y1 - 2012/6/12
N2 - P-Glycoprotein (P-gp) is often involved in multidrug resistance (MDR) to the pharmacological action of a wide number of anticancer agents. In this article, a series of molecular dynamics simulations of murines P-gp were developed, elucidating the importance of the lipid membrane and linker sequence in the protein structure stability. The behavior of several molecules inside the drug-binding pocket revealed a striking difference between substrates or modulators, and motion patterns were identified that could be correlated with conformational alterations due to substrate binding, corresponding to the initial step in the efflux mechanism. Only one "entrance gate" to the drug-binding pocket was found and, in the presence of a substrate, leads to changes in the motion patterns of the transporter into an efflux-like movement.
AB - P-Glycoprotein (P-gp) is often involved in multidrug resistance (MDR) to the pharmacological action of a wide number of anticancer agents. In this article, a series of molecular dynamics simulations of murines P-gp were developed, elucidating the importance of the lipid membrane and linker sequence in the protein structure stability. The behavior of several molecules inside the drug-binding pocket revealed a striking difference between substrates or modulators, and motion patterns were identified that could be correlated with conformational alterations due to substrate binding, corresponding to the initial step in the efflux mechanism. Only one "entrance gate" to the drug-binding pocket was found and, in the presence of a substrate, leads to changes in the motion patterns of the transporter into an efflux-like movement.
UR - http://www.scopus.com/inward/record.url?scp=84862203273&partnerID=8YFLogxK
U2 - 10.1021/ct300083m
DO - 10.1021/ct300083m
M3 - Article
AN - SCOPUS:84862203273
SN - 1549-9618
VL - 8
SP - 1853
EP - 1864
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
IS - 6
ER -