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

Abstract

P‐glycoprotein (P‐gp) has been considered an important molecular target in the reversal of multidrug resistance (MDR). As such, the development of P‐gp modulators able to restore drug sensitivity in resistant cells is still considered one of the most promising strategies for overcoming MDR. Since the identification of the P‐gp's role in MDR, several studies have been performed in order to develop effective P‐gp modulators and understand the efflux mechanism. However, no efflux modulator is still clinically available for treating multidrug‐resistant cancers. Nevertheless, recent experimental studies suggest that MDR can be surpassed by targeting a specific region within the ABC transporter structure rather than the polyspecific drug‐binding pocket. This article will focus on the information available about this new target region and on a brief overview of which scaffolds would be suitable for modulating P‐gp at this new location. WIREs Comput Mol Sci 2017, 7:e1316. doi: 10.1002/wcms.1316 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics

Structure-function relationships in ABCG2: insights from molecular dynamics simulations and molecular docking studies

“…Accordingly, we suggest that drug binding and/or ATP binding is able to induce spring-like movements that propagate conformational changes through these specific domains i) into the opposite NBD or ii) into the TM domain of the same monomer. Thus, the development of small molecules targeting these specific motifs may become a promising alternative to develop novel and specific ABCG2 efflux modulators able to tackle MDR in cancer by impairing drug-induced signal transmission, similar to what was recently suggested for P-gp 66 .…”

Theoretical insights on helix repacking as the origin of P-glycoprotein promiscuity

“…Furthermore, all P-gp variants showed significant changes in the mean contact frequencies of specific residue pairs, mainly located at the ICH2/ICH3-NBD2, an important transmission interface to couple drug binding to ATPase activity, but also being critical for P-gp folding 9,45,127,128 . Thus, another interesting approach to the modification of substrates/inhibitors is the development of allosteric modulators able to specifically interact at the ICH-NBD interfaces and impair the signal transmission between the TMD and NBDs 116 . Currently, only two scaffolds are currently known to interact in such domains, namely dihydropyridines (TMD-NBD1) 128 and flavonoids (NBD2) 129 , and additional efforts must be taken in the future to explore this hypothesis.…”

“…Concerning the ICH1-NBD1 interface, all P-gp variants showed an increase of the mean contact frequencies between I160 (ICH1) and L443 (Walker A, NBD1), both located in regions identified to be involved in ATP binding 26,116,117 . Oppositely, only in F978A and ΔF335 a decrease in contact frequencies involving D164 (ICH1) and R404 (NBD1) was observed.…”

Identification and characterisation of putative drug binding sites in human ATP-binding cassette B5 (ABCB5) transporter

“…Larger deviations were observed in the extracellular loops and intracellular coils. Large structural changes are known to occur in ABC transporters when transitioning from the resting to active state and vice versa , as evidenced by crystal structures and molecular simulation studies [2] , [20] , [31] , [39] , [47] , [87] . This could result in high plasticity in the putative binding sites of the ABCB5 transporter, affecting the accessibility of the amino acids residues that may potentially interact with the ligand and thereby, making it challenging to predict the location of binding sites by molecular docking.…”