Homology modelling of human P-glycoprotein

Abstract

P-glycoprotein (P-gp) is an ATP-binding cassette transporter that exports a huge range of compounds out of cells and is thus one of the key proteins in conferring multi-drug resistance in cancer. Understanding how it achieves such a broad specificity and the series of conformational changes that allow export to occur form major, on-going, research objectives around the world. Much of our knowledge to date has been derived from mutagenesis and assay data. However, in recent years, there has also been great progress in structural biology and although the structure of human P-gp has not yet been solved, there are now a handful of related structures on which homology models can be built to aid in the interpretation of the vast amount of experimental data that currently exists. Many models for P-gp have been built with this aim, but the situation is complicated by the apparent flexibility of the system and by the fact that although many potential templates exist, there is large variation in the conformational state in which they have been crystallized. In this review, we summarize how homology modelling has been used in the past, how models are typically selected and finally illustrate how MD simulations can be used as a means to give more confidence about models that have been generated via this approach.

About P‐glycoprotein: a new drugable domain is emerging from structural data

“…Even in MD simulations, equilibrated models of murine P‐gp and its human homology model (obtained from 4Q9H, to be published by the authors) inserted in POPC bilayers adopt much smaller NBD distances very quickly (10–20 ns), ranging from 27.5 Å down to 24.6 Å, respectively. Other MD studies with human P‐gp homology models also showed that NBD–NBD distances rapidly evolve to similar distances (30–40 Å) when inserted in a lipid bilayer, independent of the distance registered in any of the murine templates (Table ) . From these computational models, additional insights on drug recognition and efflux mechanism were able to be obtained .…”

“…Three generations of P‐gp modulators (inhibitors, Figure ) were developed, and many other molecules can be found in literature, which are reported to modulate P‐gp efflux . As P‐gp modulators are often structurally unrelated, it was initially thought that high log P values would be the major determinant for efflux modulation .…”

“…It is known that molecules bearing aromatic rings and charged amine moieties are often modulators . However, even high‐throughput, third‐generation modulators acting at the nanomolar range (e.g., tariquidar, Figure ) failed to show any clinical advantage when co‐administered with an antitumor drug.…”

“…Three generations of P-gp modulators (inhibitors, Figure 3) were developed, and many other molecules can be found in literature, which are reported to modulate P-gp efflux. 76 As P-gp modulators are often structurally unrelated, it was initially thought that high logP values would be the major determinant for efflux modulation. 105 However, initial ligand-based studies on inhibitors and analogue molecules quickly identified the presence of a basic nitrogen atom (tertiary or quaternary amine groups) and at least two aromatic rings as essential for modulating P-gp efflux.…”

In silico analysis of the binding of anthelmintics to Caenorhabditis elegans P-glycoprotein 1

“…Nevertheless, tools are needed to understand in detail the role of these proteins in ML transport, and to consider them as relevant targets for reversion of AH resistance. The release of the 3D crystal structure of Cel-Pgp-1, with good resolution (Jin et al., 2012) and QMEAN Z-score (Domicevica and Biggin, 2015) provides an opportunity to launch a sound in silico structural study of drug binding to this protein. This is particularly relevant in the view of multispecific recognition, and hence expected transport capacity, of this model protein.…”