Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening.

Here, we demonstrate a structure-based small molecule virtual screening and lead optimization pipeline using a homology model of a difficult-to-drug G-protein-coupled receptor (GPCR) target. Protease-activated receptor 4 (PAR4) is activated by thrombin cleavage, revealing a tethered ligand that activates the receptor, making PAR4 a challenging target. A virtual screen of a make-on-demand chemical library yielded a one-hit compound. From the single-hit compound, we developed a novel series of PAR4 antagonists. Subsequent lead optimization via simultaneous virtual library searches and structure-based rational design efforts led to potent antagonists of thrombin-induced activation. Interestingly, this series of antagonists was active against PAR4 activation by the native protease thrombin cleavage but not the synthetic PAR4 agonist peptide AYPGKF.

Renal cyst pseudoenhancement at 16- and 64-dector row MDCT.

OBJECTIVE: To evaluate the presence of renal cyst pseudoenhancement at 16- and 64-row multidetector computed tomography (MDCT) in patients. METHODS: MDCT images from 90 patients with renal cysts >1 cm in diameter (n=122) were retrospectively analyzed for the presence and predictors of cyst pseudoenhancement. RESULTS: Fifty-three percent of cysts 1-2 cm demonstrated pseudoenhancement (ranged from 11 to 35 HU). Cyst pseudoenhancement was more pronounced when imaged with 64-row CTs compared to 16-row CT. Cyst size, postcontrast renal parenchymal density, and number of scanner detector rows were independent predictors of pseudoenhancement. CONCLUSION: Pseudoenhancement occurs most frequently in patients with renal cysts <2 cm imaged with 64-detector-row MDCT.

Renal cyst pseudoenhancement at multidetector CT: what are the effects of number of detectors and peak tube voltage?

PURPOSE: To determine the effect of the number of detectors and peak tube voltage on renal cyst pseudoenhancement in a phantom model. MATERIALS AND METHODS: This study on computed tomographic (CT) phantoms did not require institutional review board approval. The renal compartments of a CT phantom were filled with iodinated contrast material diluted to attain attenuations of 40, 140, and 240 HU. Saline-filled cylinders simulating cysts of varying diameters (range, 0.7-3.0 cm) were serially suspended in the renal compartments and scanned at 80, 90, 100, 120, and 140 kVp in 16-detector (n = 3) and 64-detector (n = 2) CT scanners. Generalized estimating equations were used to determine predictors of cyst pseudoenhancement (defined as a >10 HU increase in cyst attenuation when the background renal attenuation increased from 40 to 140 or 240 HU). RESULTS: Pseudoenhancement was seen with higher frequency (59 [61%] of 96 cysts vs 52 [39%] of 132 cysts, P < .05) and magnitude (17 vs 13 HU, P < .005) with 64- rather than with 16-detector scanners. Pseudoenhancement was also seen with higher frequency (25 [42%] of 60 cysts vs 11 [18%] of 60 cysts, P < .005) and magnitude (18 vs 13 HU, P < .05) at 140 kVp than at 80 or 90 kVp. Cyst pseudoenhancement increased with higher background renal enhancement (P < .005) and smaller cyst diameter (P < .05). The number of detectors, peak tube voltage, renal parenchymal enhancement level, and cyst diameter were independent predictors of cyst pseudoenhancement. CONCLUSION: Lower tube voltage settings may be useful when accurate differentiation between small renal cysts and solid masses is critical, particularly for 64-detector CT scanners.