Screening And Design Of Inhibitors Targeting Sars-CoV-2 Replication And Cell Invasion Related Targets

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)causes human fatal coronavirus disease 2019(COVID-19)and poses the serious threat to global public health.COVID-19 is a novel viral disease,and there are few commercially available drugs for this disease,thus there is an urgent need to develop effective anti-SARS-CoV-2 drugs.The development of small molecule inhibitors of SARS-CoV-2 is an international frontier,and it is critical to develop inhibitors against critical and highly conserved target proteins.Viral and host proteases(i.e.,NSP10,TMPRSS2,and CTSB)play critical roles in the replication and infection of SARS-CoV-2 in host cells.The current study confirms that SARS-CoV-2 NSP10 is required for the viral replication process.In addition,blocking both TMPRSS2 and CTSB activities may be synergistically effective against SARS-CoV-2 invasion.In this study,we screened and designed compounds by molecular docking and molecular dynamics approaches,expecting to obtain lead compounds for relevant targets and provide a useful basis for screening and designing effective and safe potential inhibitors for SARS-CoV-2 replication and cell invasion related targets.The main studies are as follows:1.The virtual screening of ZINC natural compound library was performed by identifying NSP10 binding sites.Then binding energy calculations were performed to select 11 compounds with binding energies better than-80.00 kcal/mol and to evaluate ADMET properties.Based on docking score,binding free energy and ADMET properties,four representative seedling compounds were obtained.Their binding modes were analyzed,followed by 100 ns MD simulations to verify the good binding stability of the complexes.These candidate compounds have the potential to be developed as targeted SARS-CoV-2 NSP10 inhibitors.2.TMPRSS2 pharmacophore models were developed and evaluated by receptor-ligand complexes.The generated pharmacophore model was used for pharmacophore screening of SPECS compound library.Molecular docking was performed using the original ligand as reference standard to obtain four seedling compounds that interacted with key residues.Then ADMET predictions were performed and all showed good safety and druggability.Then binding modes of TM1 and TMPRSS2 were analyzed,and structural modification of TM1 resulted in compound TM2 with excellent overall performance.MD simulations and binding energy calculations were then performed to verify stable binding of compounds TM1 and TM2.These seedling compounds are expected to be TMPRSS2 inhibitors that inhibit viral membrane fusion entry.3.TMPRSS2 and CTSB pharmacophore models were constructed using receptor-ligand complexes,and the models were validated by decoy sets.The molecular library was screened using the dual-target pharmacophore,and then molecular docking was performed for secondary screening,and the six best-performing compounds in the binding model were selected.The ADMET evaluation was continued to obtain five seedling compounds.The best performing compound L1 was then subjected to binding energy calculations and MD simulations with two targets.Finally,synthetic products were performed for phenoxypropanolamine derivatives.The identified candidate compounds of TMPRSS2/CTSB may become dual-target inhibitors against SARS-CoV-2 invasion.