A substrate pharmacophore for the human sodium taurocholate co-transporting polypeptide

Abstract

Human Sodium Taurocholate Co-transporting Polypeptide (NTCP) is the main bile acid uptake transporter in the liver with the capability to translocate xenobiotics. While its inhibitor requirements have been recently characterized, its substrate requirements have not. The objectives of this study were a) to elucidate NTCP substrate requirements using native bile acids and bile acid analogs, b) to develop the first pharmacophore for NTCP substrates and compare it with the inhibitor pharmacophores, and c) to identify additional NTCP novel substrates. Thus, 18 native bile acids and two bile acid conjugates were initially assessed for NTCP inhibition and/or uptake, which suggested a role of hydroxyl pattern and steric interaction in NTCP binding and translocation. A common feature pharmacophore for NTCP substrate uptake was developed, using 14 native bile acids and bile acid conjugates, yielding a model which featured three hydrophobes, one hydrogen bond donor, one negative ionizable feature and three excluded volumes. This model was used to search a database of FDA approved drugs and retrieved the majority of the known NTCP substrates. Among the retrieved drugs, irbesartan and losartan were identified as novel NTCP substrates, suggesting a potential role of NTCP in drug disposition.

Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP

“…Unlike other bile acid transporters like OATPs, NTCP is likely not addressed by most chemotypes, as the percentage of actives identified in this study is much lower than in a similar screen for OATP inhibitors (respectively ~1% versus 7–10%) 31 . Previous computational models further support this observation 23 , 25 , 26 , 32 , 33 . Although they all could elucidate the requirement of hydrophobes and hydrogen bond acceptors, the exact number for these features varied between 3 and 1 for both in line with the current work 23 , 26 , 32 , 33 .…”

Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3

“…The K m values of bile acids, except GDCA and TDCA, were slightly lower and wider in range for OATP1B1 and OATP1B3 than NTCP (S1 Fig) [44]. The K m values of GLCA and TLCA for OATP1B1 and OATP1B3 were approximately 7–14 fold lower than K m values of GLCA and TLCA for NTCP.…”

“…(A) K m values of bile acids for OATP1B1 are shown on the X -axis, and those for NTCP cited from the previous report [44] are shown on the Y -axis; (B) K m values of bile acids for OATP1B3 are shown on the X -axis, and those for NTCP are shown on the Y -axis. Dotted line in the graphs represents 1:1 correlation.…”

Leveraging of Rifampicin-Dosed Cynomolgus Monkeys to Identify Bile Acid 3-O-Sulfate Conjugates as Potential Novel Biomarkers for Organic Anion-Transporting Polypeptides

“…Because of weaker inhibition by RIF (IC 50 $ 35.1 mM, Supplemental Table 5), less NTCP inhibition (10%-29%) is expected (Supplemental Table 6). This is an important consideration because certain BAs are known to favor NTCP over OATPs (Meier et al, 1997;Maeda et al, 2006;Dong et al, 2015: Suga et al, 2017. For example, the uptake of TCA by primary cynomolgus monkey hepatocytes was shown to be highly sodium dependent and relatively refractory to RIF (Figs.…”