Purpose COVID-19 pandemic has become worse with the difficulty of tracing the virus or phase of the coronaviral cycle inside the host, the failure of currently employed drugs over a vast population and the evolution of newer multiple strains. This work aimed to investigate and design novel molecules that can tackle coronaviral disease more effectively Methods The study was initiated with a drug repurposing approach to screen the existing drugs against multiple receptors of the initial strain, alpha coronavirus, through various in-silico analyses. The best hits were selected on their binding affinity towards most targets and their physicochemical properties. Top hits were assessed for their efficiency against multiple coronavirus strains, such as delta and Omicron and their Ligand-protein complexation stability through molecular dynamics study. They were further fragmented and subjected to fragment-based drug designing (FBDD) to give rise to novel molecules. Results Amentoflavone, Lopinavir and Teniposide were identified as the most effective ligands against multiple receptors of the corona viral protein through the drug repurposing studies. These drugs were fragmented, linked together in multiple fashions through the process of clustering and growing to give rise to some newly designed drugs. The novel compounds exhibited more affinity towards the multiple strains of coronavirus than their parent counterparts did. Conclusion Overall, the study resulted in the generation of novel moieties with promising activity towards the multiple strains of coronavirus through FBDD initiated through a multi-targeting anti-covid drug repurposing study.