Comparative Pharmacophore Modeling of Organic Anion Transporting Polypeptides: A Meta-Analysis of Rat Oatp1a1 and Human OATP1B1

Abstract

The organic anion transporting polypeptides OATPs are key membrane transporters for which crystal structures are not currently available. They transport a diverse array of xenobiotics and are expressed at the interface of hepatocytes, renal tubular cells, enterocytes, and the choroid plexus. To aid the understanding of the key molecular features for substratetransporter interactions, pharmacophore models were produced for the two OATPs that have been most extensively studied, namely rat Oatp1a1 and human OATP1B1. Literature data from Chinese hamster ovary, HeLa, human embryonic kidney 293 cells, and Xenopus laevis oocytes were used to construct pharmacophores for each individual transporter which were later merged to show similarities across cell lines for the same transporter. Additionally, meta-pharmacophores were generated from the combined datasets of each cell system used with the same transporter. The pharmacophores for each transporter consisted of hydrogen bond acceptor and hydrophobic features. There was good agreement between the merged and meta-pharmacophores containing two hydrogen bond acceptors and two or three hydrophobic features for Oatp1a1 and OATP1B1. External test sets were used to validate the individual pharmacophores. The meta-pharmacophores were also used to make predictions for molecules not included in the models and provided new molecular insight into the key features for these OATP transporters. This approach can be extended to other transporters for which limited data are available.

Structure-Based Identification of OATP1B1/3 Inhibitors

“…These findings are consistent with previous results from Chang et al (2005), who constructed a pharmacophore model for OATP1B1 and concluded that lipophilicity and hydrogen bond-acceptor strength are important properties for OATP1B1 inhibition. Our results also confirm the conclusions drawn by Badolo et al (2010), who determined that lipophilicity and the number of hydrogen bond acceptors (next to polarity and pKa) are the key properties for inhibiting the OATP1B1 probe substrate estradiol-17b-glucuronide in human hepatocytes.…”

The Development, Characterization, and Application of an OATP1B1 Inhibition Assay in Drug Discovery

“…The key descriptors for increasing OATP1B1 inhibition as determined from this in silico model are to increase the hydrogen bond-accepting strength and increase the lipophilicity. The key molecular features identified in this two-dimensional quantitative structure activity relationship approach are consistent with the work of Chang et al (2005) who by use of a three-dimensional pharmacophore approach also identified hydrogen bond accepting and hydrophobicity as key features in OATP1B1 inhibition. These key interactions are further substantiated by Gui et al (2009) who by use of a comparative molecular field analysis approach identified hydrophobicity and basicity of the side chain residues as being critical for OATP1B1 inhibition.…”

Selective Inhibition of Human Solute Carrier Transporters by Multikinase Inhibitors

“…In contrast, the inactive quinazolines lapatinib and afatinib had larger PSAs that may contribute to decreased permeability and two H-bond donor atoms; both vandetanib and lapatinib had high cLogP values. Previous studies have shown that lipophilic character is negatively correlated with inhibition of some SLC transporters (Minematsu and Giacomini, 2011) but is a determinant of substrate interactions with OATs and OATPs (Chang et al, 2005;Kaler et al, 2007;De Bruyn et al, 2013).…”