Delineating Potential De Novo Therapeutics and Repurposed Drugs Against Novel Protein Lrrc15 to Treat Sars-Cov-2

Abstract

Introduction: Sudden SARS-CoV-2 pandemic disrupted global public health; hence, searching for more effective treatments is urgently needed. Objective: Recently, a new host protein LRRC15 has been identified, facilitating viral attachment and cellular invasion and hence can be a good target against SARS-CoV-2. In this study, design some potential inhibitors against LRRC15. objective: Recently a new host protein LRRC15 has been identified which facilitates the viral attachment and cellular invasion and hence can be a good target against SARS-CoV-2. In this study, design some potential inhibitors against LRRC15. Method: Here, we explored three strategies to find potential inhibitors against LRRC15, including the repurposing of ACE2 inhibitors, structure-based de novo drug generation, and virtual screening of three chemical libraries (ZINC Trial, ZINC Fragments, and Enamine HTSC). method: Here, we explored three strategies to find potential inhibitor against LRRC15 including repurposing of ACE2 inhibitors, structure based de novo drug generation and virtual screening of three chemical libraries (ZINC Trial, ZINC Fragments and Enamine HTSC). Result: Based on binding affinity Benazepril (-7.7 kcal/mol) was chosen as a final repurpose drug candidate, and ten de novo drugs (-8.9 to -8.0 kcal/mol) and 100 virtually screened drugs (-11.5 to -10.7 kcal/mol) were elected for further ADMET and drug likeliness investigation. After filtering, Z131403838 and Z295568380 were chosen as final drug candidates, and de novo drugs were further optimized. Optimization, re-docking, and pharmacokinetic analysis confirmed L-2 and L-36 as the best hit de novo drug candidates. Furthermore, all five final drugs demonstrated stable receptor-drug complex stability in molecular dynamics simulation. result: : Based on binding affinity Benazepril (-7.7 kcal/mol) was chosen as a final repurpose drug candidate; and, ten de novo drugs (-8.9 to -8.0 kcal/mol) and 100 virtually screened drug (-11.5 to -10.7 kcal/mol) were elected for further ADMET and drug likeliness investigation. After filtering, Z131403838 and Z295568380 were chosen as final drug candidate and de novo drugs were further optimized. Optimization, re-docking and pharmacokinetic analysis confirmed L-2 and L-36 as the best hit de novo drug candidates. Furthermore, all the five final drugs demonstrated stable receptor-drug complex stability in molecular dynamics simulation. Conclusion: Effective treatment options are necessary to combat the SARS-CoV-2 epidemics. All the compounds presented in this study appeared to be promising inhibitorpromising inhibitors against LRRC15, though the future clinical investigation is needed toensure the biological effectiveness. conclusion: Effective treatment options are necessary to combat the SARS-CoV-2 epidemics. All the compounds presented in this study appeared to be promising inhibitor against LRRC15, though future clinical investigation is needed to assure the biological effectiveness.