Identification of non-macrocyclic small molecule inhibitors against the NS3/4A serine protease of hepatitis C virus through in silico screening.
Drug discovery and design for inhibition of the Hepatitis C Virus (HCV) NS3/4A serine protease is a major challenge. The broad, shallow, and generally featureless nature of the active site makes it a difficult target for "hit" selection especially using standard docking programs. There are several macrocyclic NS3/4A protease inhibitors that have been approved or are in clinical trials to treat chronic HCV (alone or as combination therapy), but most of the current therapies for HCV infection have untoward side effects, indicating a continuing medical need for the discovery of novel therapeutics with improved efficacy. In this study, we designed and implemented a two-tiered and progressive docking regime that successfully identified five non-macrocyclic small molecules that show inhibitory activity in the low micromolar range. Of these, four compounds show varying inhibition against HCV subgenotypes 1b, 1a, 2a, and 4d. The top inhibitor (3) has an IC(50) value of 15 μM against both subgenotypes 1b and 2a of the NS3/4A protease enzyme. Another inhibitor, 1, inhibits all four subgenotypes with moderate activity, showing highest activity for genotype 2a (24 μM). The five inhibitors presented in this study could be valuable candidates for future hit to lead optimization. Additionally, enzyme-inhibitor interaction models presented herein provide key information regarding structural differences between the active sites of the NS3/4A protease of the HCV subgenotype 1a and 1b that might explain the variable inhibitory activity between subgenotypes of the small molecule inhibitors identified here.
Center for Pharmaceutical Biotechnology, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland Ave., M/C 870, Chicago, Illinois 60607, USA.
Rima
R
Chaudhuri
Hyun
H
Lee
Lena
L
Truong
Jaime
J
Torres
Kavankumar
K
Patel
Michael E
ME
Johnson
D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D016174:Hepacivirus / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology*; D014584:User-Computer Interface; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases