Application of an integrated cheminformatics-molecular docking approach for discovery for physicochemically similar analogs of fluoroquinolones as putative HCV inhibitors |
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| Institution: | 1. Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan;2. Department of Biochemistry, University of Karachi, Karachi, Pakistan;3. Medical College, Aga Khan University, Karachi, Pakistan;4. National Center of Proteomics, University of Karachi, Karachi, Pakistan;5. Department of Biological Sciences, Nazarbayev University School of Medicine, Nazarbayev University, Astana, Kazakhstan;1. ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108, USA;2. Abbott Molecular Inc, 1350 E. Touhy Avenue, Des Plaines, IL, 60018, USA;3. Department of Neuroscience, Mayo Clinic, 4500 Pablo Road, Jacksonville, FL, 32224, USA;4. Department of Pathology, University of Utah, 15 North Medical Drive East, Salt Lake City, UT 84112, USA;1. Institute of Strength Physics and Materials Science, The Russian Academy of Sciences, pr. Academicheskii 2/4, 634055 Tomsk, Russia;2. National Research Tomsk Polytechnic University, pr. Leninа 30, 634050 Tomsk, Russia;3. National Research Tomsk State University, pr. Leninа 36, 634050 Tomsk, Russia;1. Department of Physics, Tripura University, Suryamaninagar, 799022, Tripura, India;2. Department of Physics, Government Degree College, Kamalpur, 799285, Tripura, India;3. Department of Physics, Women''s College, Agartala, 799001, Tripura, India;1. School of Physics and Technology, University of Jinan, Jinan 250022, China;2. College of Physics and Electronics, Shandong Normal University, Jinan 250014, China |
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| Abstract: | BackgroundHepatitis C Virus (HCV) infection is a major public health concern across the globe. At present, direct-acting antivirals are the treatment of choice. However, the long-term effect of this therapy has yet to be ascertained. Previously, fluoroquinolones have been reported to inhibit HCV replication by targeting NS3 protein. Therefore, it is logical to hypothesize that the natural analogs of fluoroquinolones will exhibit NS3 inhibitory activity with substantially lesser side effects.MethodIn this study, we tested the application of a recently devised integrated in-silico Cheminformatics-Molecular Docking approach to identify physicochemically similar natural analogs of fluoroquinolones from the available databases (Ambinter, Analyticon, Indofines, Specs, and TimTec). Molecular docking and ROC curve analyses were performed, using PatchDock and Graphpad software, respectively, to compare and analyze drug-protein interactions between active natural analogs, Fluoroquinolones, and HCV NS3 protein.ResultIn our analysis, we were able to shortlist 18 active natural analogs, out of 10,399, that shared physicochemical properties with the template drugs (fluoroquinolones). These analogs showed comparable binding efficacy with fluoroquinolones in targeting 32 amino acids in the HCV NS3 active site that are crucial for NS3 activity. Our approach had around 80 % sensitivity and 70 % specificity in identifying physicochemically similar analogs of fluoroquinolones.ConclusionOur current data suggest that our approach can be efficiently applied to identify putative HCV drug inhibitors that can be taken for in vitro testing. This approach can be applied to discover physicochemically similar analogs of virtually any drug, thus providing a speedy and inexpensive approach to complement drug discovery and design, which can tremendously economize on time and money spent on the screening of putative drugs. |
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| Keywords: | Cheminformatics Molecular docking Drug discovery Antiviral agents |
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