title: In silico identification and evaluation of leads for the simultaneous inhibition of protease and helicase activities of HCV NS3/4A protease using complex based pharmacophore mapping and virtual screening.
abstract: Hepatitis C virus (HCV) infection is an alarming and growing threat to public health. The present treatment gives limited efficacy and is poorly tolerated, recommending the urgent medical demand for novel therapeutics. NS3/4A protease is a significant emerging target for the treatment of HCV infection. This work reports the complex-based pharmacophore modeling to find out the important pharmacophoric features essential for the inhibition of both protease and helicase activity of NS3/4A protein of HCV. A seven featured pharmacophore model of HCV NS3/4A protease was developed from the crystal structure of NS3/4A protease in complex with a macrocyclic inhibitor interacting with both protease and helicase sites residues via MOE pharmacophore constructing tool. It consists of four hydrogen bond acceptors (Acc), one hydrophobic (Hyd), one for lone pair or active hydrogen (Atom L) and a heavy atom feature (Atom Q). The generated pharmacophore model was validated by a test database of seventy known inhibitors containing 55 active and 15 inactive/least active compounds. The validated pharmacophore model was used to virtually screen the ChemBridge database. As a result of screening 1009 hits were retrieved and were subjected to filtering by Lipinski's rule of five on the basis of which 786 hits were selected for further assessment using molecular docking studies. Finally, 15 hits of different scaffolds having interactions with important active site residues were predicted as lead candidates. These candidates having unique scaffolds have a strong likelihood to act as further starting points in the development of novel and potent NS3/4A protease inhibitors.
authors.affiliation: Computational Medicinal Chemistry Laboratory, Department of Biochemistry Abdul Wali Khan University Mardan, Mardan, Khyber Pakhthunkhwa, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.affiliation: Computational Medicinal Chemistry Laboratory, Department of Biochemistry Abdul Wali Khan University Mardan, Mardan, Khyber Pakhthunkhwa, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Riaz
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, University of Karachi, Karach, Sindh, Pakistan.
authors.forename: Reaz
authors.initials: R
authors.lastname: Uddin
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, University of Karachi, Karach, Sindh, Pakistan.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul-Haq
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D020134:Catalytic Domain; D062126:Databases, Chemical; D015195:Drug Design; D016174:Hepacivirus / Q000737:chemistry* / Q000201:enzymology; D057166:High-Throughput Screening Assays; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000737:chemistry*; D014584:User-Computer Interface; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus