Screening Of Broad-spectrum Anti Coronavirus Small Molecule Inhibitors Based On 3CL Protease Structure

The COVID-19 epidemic has become the third global epidemic which was caused by coronaviruses in the 21 st century.The epidemic has lasted for a long time and spread widely.SARS-Co V-2 was highly contagious and easy to mutate.Although some drugs have been approved and applied in clinical practice continuously,either the effect is unsatisfactory(such as Remdesivir and Molnupiravir),or the stability in vivo is poor,which requires the combination of drugs(such as Paxlovid).Therefore,new anti-coronavirus drugs still need to be developed in the future.Meanwhile,the development of effective broad-spectrum anti coronavirus drugs is not only an urgent need,but also a preparation for unknown new coronavirus infection again in the future.Based on the highly conserved structure of 3CLpro of coronavirus,the screening of broad-spectrum anti coronavirus small molecule inhibitors was carried out in this subject.The compounds were obtained that are bound to3 CLpro by virtual molecular docking.Then these compounds were screened and optimized in vitro assays to get the lead compounds with development potential.Then their broad-spectrum anti coronavirus activities were verified.The following results were obtained:1.A virtual screening model based on the structure of 3CLpro was established,and 456 potentially active compounds were obtained.2.17 kinds of natural products and other small molecular compounds with remarkable enzyme inhibition effect in vitro were obtained by enzyme activity experiments.5 among them were dihydro-4H-thieno[2,3-e]indazole compounds,which laid a foundation for the development of broad-spectrum anti coronavirus drugs with new molecule scaffolds.3.Compounds with remarkable inhibitory activities on pangolin coronavirus GX＿P2V,common coronavirus HCo V-OC43,common coronavirus HCo V-229 E and SARS-Co V-2 were obtained by cell assays.4.A technical system for screening and evaluating 3CLpro inhibitors was established,which will provide support for the research and development of this kind of broad-spectrum anti coronavirus drugs.