Structure−Function Relationships of Multidrug Resistance P-Glycoprotein

Abstract

The direct structure-function relationships of P-glycoprotein (P-gp) are presently unknown. In this paper two P-gp models are described: a homology model based on the Escherichia coli MsbA lipid transporter and a model based on the cross-linking results of Loo and Clarke. The pharmacophore pattern for the H-site (Hoechst 33342) is derived and binding sites on the transmembrane domains TM5 and TM11 are identified. Binding sites of rhodamines are also proposed on TM6 and TM12 in accordance with the published data. Location of the binding sites is opposite in both models, suggesting that TMs undergo rotation exposing the substrate bound from the membrane to the pore. It has been concluded that the models derived represent two different functional states of P-gp corresponding to nucleotide-free and nucleotide-bound P-gp. A qualitative correspondence to the P-gp crystallographic structure at 20 A resolution is found. A hypothesis is proposed about rearrangement of TMs upon state transition.

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

“…Crystal structures of these proteins indicate that they interact with drugs through van der Waals interactions and hydrophobic stacking (426). However, models based on chemical cross-linking studies, photolabeling experiments, homology modeling, and pharmacophore patterns (266) suggest that MDR1/Pgp makes different interactions with different drugs, implying the involvement of several, partially overlapping residues. Thus each substrate appears to define a unique niche in the complex binding pocket through an "inducedfit" mechanism (216,272).…”

Structure–Activity Relationships of Tariquidar Analogs as Multidrug Resistance Modulators

“…Pajeva et al (48) have used these facts to develop a minimal ligand pharmacophore for the H-binding site of P-gp. Figure 3a, b shows the structure of Hoechst 33342 and QB 102 together with the pharmacophoric points identified from overlays of Hoechst 33342 and QB compounds.…”

Computational models for predicting drug transport mediated by P-glycoprotein

“…Iako je ovaj model razvijen korišćenjem relativno malog broja struktura, naš rad na razvoju modela za transport Pgp-om ukazao je da trodimenzionalni deskriptori izvedeni iz predloženih farmakofora mogu značajno unaprediti predviđanja globalnih modela [47]. Većina drugih farmakofornih modela u literaturi predložena je za specifična, pretpostavljena vezivna mesta Pgp-a [69][70][71]. Do sada predloženi globalno primenjivi farmakoforni modeli zasnivaju se na pristupu koriščenja skupa (ansambla) velikog broja pojedinačnih farmakofora.…”