Figure 12
From: Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor
(a) Flow chart of this investigation. A small molecule database is employed to identify UT-B inhibitors via HTVS and high-throughput screening. (b) Inhibitors were used to map novel inhibitor binding sites by in silico methods. Inhibitor binding site was found to overlap a part of the urea binding site. A cryptic binding pocket, such as FGD, was discovered to be important in anchoring an inhibitor that contains residues TRP286 and ASN289. (c) Quantitative structure activity relationship suggested a hydrogen bond acceptor favored property is located near FGD which provides proper interaction pocket to PU21. The inhibition mechanism hypothesis was supported by fine-grained molecular dynamics. (d) All atom simulations suggest small inhibitors, such as PU21, might generate induced-fit mechanisms in urea transportation blocking. By generating steric hindrance directly towards urea binding site, other larger inhibitors are able to generate inhibition activity similar to PU21. This cross-species study discovered that the migration pathway of PU168 and PU474 might be interrupted by residue PHE198 in either (e) mouse or (f) rat model.
