Journal of Petroleum & Environmental Biotechnology

Discovery of new small molecule inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase: Pharmacophore modeling, 3D-QSAR studies dnd high-throughput screening

J. T. Patrisha, K. Sridevi, Shruthi Kakkan, D. Sriram and P. Yogeeswari

: Agrotechnol

Abstract:

Hepatitis C Virus (HCV), a blood-borne pathogen belonging to the Flaviviridae family of viruses, is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and liver cancer. The current HCV therapy suffers from inadequate sustained viral response rate, in particular for patients infected with genotype 1 HCV, along with significant side effects, resulting in a continuing medical treatment. Our research has been focused on identifying novel small molecule inhibitors of the HCV NS5B protein, a virally encoded RNA-dependent RNA polymerase (RdRp), the activity of which is critical for the replication of the virus. In this study, a 3D pharmacophore mapping studies were undertaken for different series of synthetic derivatives. A five point pharmacophore with two hydrogen bond acceptors (A), one hydrogen bond donor (D), and two aromatic rings (R) as pharmacophoric features was developed. The pharmacophore was validated using enrichment calculation which yielded a statistically significant 3D-QSAR model with good correlation coefficient (R 2 = 0.9715) for training set compounds. The model showed excellent predictive power (Q 2 = 0.6063). The model was then employed as 3D search query to screen against public and In-House libraries (Asinex, BITS database) in-order to identify a new scaffold. Top ranked hits were selected, synthesized and were evaluated for their enzyme inhibitory activity against HCV Protease. Inhibitors with IC50 value >50nM were considered as potential inhibitors forHCV Protease. The backbone structural scaffold features and contour maps obtained from the 3D QSAR model could serve as template to design novel small molecule inhibitors for HCV Protease

Biography :

J. T. Patrisha has completed her M.Sc. (Chemistry) from Annamalai University, Tamilnadu. Currently, she is pursuing Ph.D. from Department of Pharmacy, Birla Institute of Technology & Science-Pilani (BITS-Pilani), Hyderabad campus, Jawahar nagar, Hyderabad under the guidance of Prof. P. Yogeeswari since March, 2010. Her research area of interest is antimicrobial drug discovery