Title:Delineating Potential de novo Therapeutics and Repurposed Drugs Against
Novel Protein LRRC15 to Treat SARS-CoV-2
Volume: 21
Issue: 9
Author(s): Maliha Afroj Zinnia and Abul Bashar Mir Md. Khademul Islam*
Affiliation:
- Department of Genetic Engineering & Biotechnology,
University of Dhaka, Dhaka, Bangladesh
Keywords:
SARS-CoV-2, LRRC15, ACE2, molecular docking, molecular dynamics simulation, ADMET analysis.
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.
Methods: 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).
Results: 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.
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.
