Abstract
Hepatic organic anion transporting polypeptides—OATP1B1, OATP1B3, and OATP2B1—are expressed at the basolateral membrane of hepatocytes, being responsible for the uptake of a wide range of natural substrates and structurally unrelated pharmaceuticals. Impaired function of hepatic OATPs has been linked to clinically relevant drug–drug interactions leading to altered pharmacokinetics of administered drugs. Therefore, understanding the commonalities and differences across the three transporters represents useful knowledge to guide the drug discovery process at an early stage. Unfortunately, such efforts remain challenging because of the lack of experimentally resolved protein structures for any member of the OATP family. In this study, we established a rigorous computational protocol to generate and validate structural models for hepatic OATPs. The multistep procedure is based on the systematic exploration of available protein structures with shared protein folding using normal-mode analysis, the calculation of multiple template backbones from elastic network models, the utilization of multiple template conformations to generate OATP structural models with various degrees of conformational flexibility, and the prioritization of models on the basis of enrichment docking. We employed the resulting OATP models of OATP1B1, OATP1B3, and OATP2B1 to elucidate binding modes of steroid analogs in the three transporters. Steroid conjugates have been recognized as endogenous substrates of these transporters. Thus, investigating this data set delivers insights into mechanisms of substrate recognition. In silico predictions were complemented with in vitro studies measuring the bioactivity of a compound set on OATP expressing cell lines. Important structural determinants conferring shared and distinct binding patterns of steroid analogs in the three transporters have been identified. Overall, this comparative study provides novel insights into hepatic OATP-ligand interactions and selectivity. Furthermore, the integrative computational workflow for structure-based modeling can be leveraged for other pharmaceutical targets of interest.
Highlights
Solute carriers (SLC) are increasingly recognized for their pivotal role in compound pharmacokinetics, given their involvement in drug absorption, disposition, metabolism, elimination, clinically relevant drug−drug interactions, and related organ toxicities.[1,2] Here, we focus on a triad of organic anion transporting polypeptides of the SLCO (SLC21) superfamily
We present an integrative computational approach, involving a systematic exploration of available structures with major facilitator superfamily (MFS)-fold by normal-mode analysis, construction of multiple OATP models based on alternate conformations of selected templates, prioritization of the models on the basis of enrichment docking, and an in-depth analysis of molecular interactions for steroid analogs
An increased flexibility at the TMH1/TMH2 interface was found to be an important determinant which contributes to the intrinsic dynamics of MFS proteins
Summary
Solute carriers (SLC) are increasingly recognized for their pivotal role in compound pharmacokinetics, given their involvement in drug absorption, disposition, metabolism, elimination, clinically relevant drug−drug interactions, and related organ toxicities.[1,2] Here, we focus on a triad of organic anion transporting polypeptides of the SLCO (SLC21) superfamily. OATP1B1 (SLCO1B1 gene), OATP1B3 (SLCO1B3 gene), and OATP2B1 (SLCO2B1 gene) are expressed at the basolateral membrane of hepatocytes, mediating the cellular uptake of a broad spectrum of endogenous substrates and xenobiotics.[3−5] Endogenous compounds include bilirubin, bile acids, steroid conjugates, and hormones. Drugs transported by hepatic OATPs are structurally and functionally quite heterogeneous, such as statins (pitavastatin, rosuvastatin, fluvastatin),[6] antihistamines (fexofenadine),[7] anticancer agents (SN-38, paclitaxel, imatinib),[8] antibiotics (rifampicin, clarithromycin, benzylpenicillin),[9] or anti-inflammatory drugs (ibuprofen, diclofenac, lumiracoxib).[10] OATP-mediated drug−drug interactions represent a challenge for drug development. The computational prediction of whether a certain drug might interact with hepatic OATPs is a promising approach at the early stage in the drug discovery pipeline to Received: March 29, 2021 Published: June 9, 2021
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