Identification of Non-Macrocyclic Small Molecule Inhibitors against the NS3/4A Serine Protease of Hepatitis C Virus through in Silico Screening
| Autor: | Michael E. Johnson, Hyun Lee, Rima Chaudhuri, Lena Truong, Kavankumar Patel, Jaime Torres |
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| Rok vydání: | 2012 |
| Předmět: |
General Chemical Engineering
medicine.medical_treatment Hepatitis C virus Drug Evaluation Preclinical Hepacivirus Viral Nonstructural Proteins Library and Information Sciences Pharmacology medicine.disease_cause Small Molecule Libraries Inhibitory Concentration 50 User-Computer Interface Catalytic Domain medicine Protease Inhibitors Serine protease NS3 Protease biology Drug discovery Computational Biology General Chemistry Hit to lead Small molecule Virology Computer Science Applications Molecular Docking Simulation Docking (molecular) biology.protein |
| Zdroj: | Journal of Chemical Information and Modeling. 52:2245-2256 |
| ISSN: | 1549-960X 1549-9596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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