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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Delineating Potential de novo Therapeutics and Repurposed Drugs Against Novel Protein LRRC15 to Treat SARS-CoV-2

Author(s): Maliha Afroj Zinnia and Abul Bashar Mir Md. Khademul Islam*

Volume 21, Issue 9, 2024

Published on: 18 April, 2023

Page: [1502 - 1520] Pages: 19

DOI: 10.2174/1570180820666230223120829

Price: $65

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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.

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