Accelerated discovery of novel coronavirus inhibitors

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) has created an unprecedented global health and economic crisis. The molecular understanding of the biology and pathology of the SARS-CoV-2 virus has been steadily advancing ever since the outbreak. Even though the vaccination strategy has been very effective in limiting the spread, the development of pan-coronaviral therapeutics is essential for tackling viral mutations and future outbreaks. Structure-based virtual screening is an effective method that helps in novel drug design, and it significantly reduces the cost and time taken in the drug discovery process. Recent studies have shown that expanding the screening space to ultra -large compound libraries (100 million compounds and above) results in significantly higher affinity hits, eventually leading to potent drugs. Since the Development of stand-alone as well as combinational therapies are essential to tackle future coronavirus pandemics, this project follows a multi-pronged approach, where multiple protein targets on the SARS-CoV-2 virus are targeted. The project employs - VirtualFlow - a computational drug discovery platform to quickly screen billions of molecules virtually against multiple viral targets in parallel. The key viral proteins that are targeted in this project are the spike protein- which engages with the host receptor to facilitate the entry of the virus into cells, and multiple components of the viral replication-transcription complex that are essential for the viral amplification. The top virtual hits against these key viral targets will be experimentally validated for target engagement using structural and biophysical assays and for efficacy in cell-based assays. Once a pool of top hits for these multiple targets are obtained, they will be tested for drug combination synergy with lead molecules belonging to multiple regimen classes. Special emphasis will be given to broad-spectrum antiviral activity against multiple coronavirus strains. Cognizant of the urgency to find a cure for COVID-19 and develop therapeutics against future outbreaks, the proposed research program is designed to have expedited results.

The global health and economic crisis brought about by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is unparalleled. Since the outbreak, there has been continuous progress in understanding the molecular aspects of SARS-CoV-2's biology and pathology. Despite the success of vaccination in curbing its spread, it's crucial to develop therapeutics that can address viral mutations and future outbreaks. Structure-based virtual screening is a valuable method for innovative drug design, offering substantial cost and time savings in drug discovery. Recent research has demonstrated that expanding the screening process to extremely large compound libraries (containing 100 million compounds or more) yields more potent drugs. To combat potential future coronavirus pandemics, a multi-faceted approach is necessary. This project adopted a comprehensive strategy targeting various protein sites on the SARS-CoV-2 virus. The project utilized the 'VirtualFlow' computational drug discovery platform to virtually screen billions of molecules against multiple viral targets concurrently. Two pivotal protein targets for drug discovery in this project were: 1) the spike protein, which plays a vital role in viral entry, and 2) nsp10, a cofactor protein with essential functions in viral exoribonuclease and methyl transferase activities. Throughout the project's duration, an integrated approach combining structural biology, computational biology, and medicinal chemistry led to the identification of scaffolds with micromolar inhibitory potential against the virus. The virtual hits were subjected to biophysical assays, and further characterization involved biochemical, biophysical, and structural tools. Notably, there was a strong focus on establishing broad-spectrum antiviral effectiveness against multiple coronavirus strains.