A new method for induced fit docking (GENIUS) and its application to virtual screening of novel HCV NS3-4A protease inhibitors.

Hepatitis C virus (HCV) is an etiologic agent of chronic liver disease, and approximately 170 million people worldwide are infected with the virus. HCV NS3-4A serine protease is essential for the replication of this virus, and thus has been investigated as an attractive target for anti-HCV drugs. In this study, we developed our new induced-fit docking program (genius), and applied it to the discovery of a new class of NS3-4A protease inhibitors (IC(50)=1-10 µM including high selectivity index). The new inhibitors thus identified were modified, based on the docking models, and revealed preliminary structure-activity relationships. Moreover, the genius in silico screening performance was validated by using an enrichment factor. We believe our designed scaffold could contribute to the improvement of HCV chemotherapy.

Two flavonoids extracts from Glycyrrhizae radix inhibit in vitro hepatitis C virus replication.

AIM: Traditional herbal medicines have been used for several thousand years in China and other Asian countries. In this study we screened herbal drugs and their purified compounds, using the Feo replicon system, to determine their effects on in vitro HCV replication. METHODS: We screened herbal drugs and their purified extracts for the activities to suppress hepatitis C virus (HCV) replication using an HCV replicon system that expressed chimeric firefly luciferase reporter and neomycin phosphotransferase (Feo) genes. We tested extracts and 13 purified compounds from the following herbs: Glycyrrhizae radix; Rehmanniae radix; Paeoniae radix; Artemisiae capillari spica; and Rhei rhizoma. RESULTS: The HCV replication was significantly and dose-dependently suppressed by two purified compounds, isoliquiritigenin and glycycoumarin, which were from Glycyrrhizae radix. Dose-effect analyses showed that 50% effective concentrations were 6.2 +/- 1.0 microg/mL and 15.5 +/- 0.8 microg/mL for isoliquiritigenin and glycycoumarin, respectively. The MTS assay did not show any effect on cell growth and viability at these effective concentrations, indicating that the effects of the two compounds were specific to HCV replication. These two compounds did not affect the HCV IRES-dependent translation nor did they show synergistic action with interferon-alpha. CONCLUSION: Two purified herbal extracts, isoliquiritigenin and glycycoumarin, specifically suppressed in vitro HCV replication. Further elucidation of their mechanisms of action and evaluation of in vivo effects and safety might constitute a new anti-HCV therapeutics.

[Interstitial laser coagulation for benign prostatic hyperplasia: clinical results of the Indigo diode laser system].

We report our experience with interstitial laser coagulation of the prostate (ILCP) using an Indigo 830j diode laser system for benign prostatic hyperplasia (BPH). From March 1998 to November 2000, we treated 45 patients between 51 and 95 years old (average 71.5) with symptomatic BPH. The mean prostatic volume before ILCP was 62.0 cm3. We experienced no serious complications. Three months after ILCP, the mean international prostate symptom score (I-PSS) quality of life (QOL) index and post-void residual volume (PVR) decreased significantly from 18.0 to 9.2, from 4.4 to 2.1 and from 103.6 ml to 44.5 ml, respectively. The mean maximum flow rate (MFR) increased from 7.6 ml/sec at baseline to 9.2 ml/sec 3 months after ILCP, but the difference was not statistically significant. Before and after ILCP, 8 patients were available to evaluate pressure-flow study data. The detrusor pressure at the maximum flow rate decreased significantly from 118.3 cmH2O at baseline to 78.6 cmH2O 3 months after ILCP. The improvement of the I-PSS, QOL index, MFR and PVR continued and at 24 months reached 5.7, 1.8, 11.6 ml/sec and 54.6 ml, respectively. In our assessment of the questionnaire addressing the patient's satisfaction after the treatment, the majority of the patients who answered the questionnaire were pleased with the results of ILCP. We assessed the relation of the overall treatment efficacy with the number of punctures and the total amount of the laser energy delivered, but we did not find any relation. Our clinical results suggest that the ILCP using Indigo 830j is an effective modality and the short-term treatment efficacy is favorable.