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Road Map for the Structure-Based Design of Selective Covalent HCV NS3/4A Protease Inhibitors

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Abstract

Over the last 2 decades, covalent inhibitors have gained much popularity and is living up to its reputation as a powerful tool in drug discovery. Covalent inhibitors possess many significant advantages including increased biochemical efficiency, prolonged duration and the ability to target shallow, solvent exposed substrate-binding domains. However, rapidly mounting concerns over the potential toxicity, highly reactive nature and general lack of selectivity have negatively impacted covalent inhibitor development. Recently, a great deal of emphasis by the pharmaceutical industry has been placed toward the development of novel approaches to alleviate the major challenges experienced through covalent inhibition. This has unexpectedly led to the emergence of “selective” covalent inhibitors. The purpose of this review is not only to provide an overview from literature but to introduce a technical guidance as to how to initiate a systematic “road map” for the design of selective covalent inhibitors which we believe may assist in the design and development of optimized potential selective covalent HCV NS3/4A viral protease inhibitors.

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Acknowledgements

The authors acknowledge the National Research Foundation for their financial support.

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Authors and Affiliations

  1. Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa

    Letitia Shunmugam, Pritika Ramharack & Mahmoud E. S. Soliman

  2. College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, FAMU, Tallahassee, FL, 32307, USA

    Mahmoud E. S. Soliman

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  1. Letitia Shunmugam
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Shunmugam, L., Ramharack, P. & Soliman, M.E.S. Road Map for the Structure-Based Design of Selective Covalent HCV NS3/4A Protease Inhibitors. Protein J 36, 397–406 (2017). https://doi.org/10.1007/s10930-017-9736-8

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