Drug-design strategies against viral diseases

The current study deals with the drug design strategies against viruses belong to the vector-borne diseases, mainly Flaviviridae and those which cause viral haemorrhagic fevers (VHFs), including Ebola and Crimean-Congo viruses which have mortality rates up to 90%. Despite a high mortality rate, no licensed antiviral drugs or vaccines are currently available against these viruses. Although phenomenal efforts have been made in recent years in therapeutic advancements. Modern computational drug discovery has proven to accelerate the challenging process at any stage in the preclinical development of drug candidates. The availability of crystal structures for key proteins involved in viral life cycle made it possible to formulate inhibitor design studies. A multi-pronged developed structure and ligand-based drug design approaches were utilized followed by molecular dynamics simulations against Zika-protease and identified one analogue showed promising activity (IC50 = 10 µM) against Zika virus which lacks cytotoxicity (CC50 > 100 µM). Whereas, in-silico approaches also identified potential hits against Ebola, Congo virus and recently emerged SARS-CoV-2, which warrant in-vitro evaluations. The study was also extended to other viral diseases like HIV, which identified HIV entry inhibitors by targeting co-receptors, including very selective C-C chemokine receptor type 5, CCR5 antagonist (IC50 = 10.6 µM), and dual CCR5/CXCR4 antagonist. The lead compounds identified after hierarchical drug design strategies with potential antiviral activity profile will be further optimized, and the 3D-QSAR model might leads to identify potential compounds with improved specificity and activity.

Author(s): Muhammad Usman Mirza

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