Abstract
Human coronaviruses represent a significant disease burden; however, there is currently no antiviral strategy to combat infection. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) less than 10 years later demonstrates the potential of coronaviruses to cross species boundaries and further highlights the importance of identifying novel lead compounds with broad spectrum activity. The coronavirus 3CLpro provides a highly validated drug target and as there is a high degree of sequence homology and conservation in main chain architecture the design of broad spectrum inhibitors is viable. The ZINC drugs-now library was screened in a consensus high-throughput pharmacophore modeling and molecular docking approach by Vina, Glide, GOLD and MM-GBSA. Molecular dynamics further confirmed results obtained from structure-based techniques. A highly defined hit-list of 19 compounds was identified by the structure-based drug design methodologies. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds is bioactive is excellent. Additionally, the compounds segregate into 15 significantly dissimilar (p < 0.05) clusters based on shape and features, which represent valuable scaffolds that can be used as a basis for future anti-coronaviral inhibitor discovery experiments. Importantly though, the enriched subset of 19 compounds identified from the larger library has to be validated experimentally.
Highlights
Coronaviruses (CoV) affect a diverse group of animal hosts, and cause a plethora of diseases in animals including progressive peritonitis, acute and chronic hepatitis, gastroenteritis, nephritis, and encephalitis [1]
Lead compounds that have shown promise as potential inhibitors of the 3CLpro of coronaviruses are largely represented by peptidomimetic compounds that covalently alter the thiolate anion of the active Cys residue [19]
Few studies have focused on the development of broad spectrum, noncovalent inhibitors and, to our knowledge, none have aimed to prioritize the identification of broad spectrum lead compounds that inhibit the 3CLpro related to the coronaviruses that most frequently affect humans, namely 229E, OC43, NL63 and HKU1
Summary
Coronaviruses (CoV) affect a diverse group of animal hosts, and cause a plethora of diseases in animals including progressive peritonitis, acute and chronic hepatitis, gastroenteritis, nephritis, and encephalitis [1]. Four human coronaviruses (HCoV; 229E, OC43, NL63 and HKU1) are endemic in the human population and are mainly associated with mild, self-limiting respiratory illnesses. Another two human coronaviruses, namely severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, cause severe respiratory syndromes and present a significant threat with their high fatality rates. Majority of infections are associated with self-limiting upper respiratory tract disease or “the common cold” but can present with high morbidity outcomes of the lower respiratory tract including bronchiolitis, pneumonia, [4,5,6], asthmatic exacerbations [7] acute exacerbations of chronic obstructive pulmonary disease (COPD) [8] and croup in HCoV-NL63 infected patients [9], and commonly results in hospitalization. Febrile seizures have been reported for most human coronaviruses but the significance of HKU1 is alarming with one study indicating that 50% of patients infected with HKU1 experience febrile seizures [7]
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