Insights on P-glycoproteins efflux mechanism obtained by molecular dynamics simulations

Ricardo J. Ferreira, Maria José U. Ferreira, Daniel J.V.A. Dos Santos

Research output: Contribution to journalArticlepeer-review

110 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1853-1864
Number of pages12
JournalJournal of Chemical Theory and Computation
Volume8
Issue number6
DOIs
Publication statusPublished - 12 Jun 2012
Externally publishedYes

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