Computational Docking as a Tool in Guiding the Drug Design of Rutaecarpine Derivatives as Potential SARS-CoV-2 Inhibitors

Molecules. 2024 Jun 3;29(11):2636. doi: 10.3390/molecules29112636.

Abstract

COVID-19 continues to spread around the world. This is mainly because new variants of the SARS-CoV-2 virus emerge due to genomic mutations, evade the immune system and result in the effectiveness of current therapeutics being reduced. We previously established a series of detection platforms, comprising computational docking analysis, S-protein-based ELISA, pseudovirus entry, and 3CL protease activity assays, which allow us to screen a large library of phytochemicals from natural products and to determine their potential in blocking the entry of SARS-CoV-2. In this new screen, rutaecarpine (an alkaloid from Evodia rutaecarpa) was identified as exhibiting anti-SARS-CoV-2 activity. Therefore, we conducted multiple rounds of structure-activity-relationship (SAR) studies around this phytochemical and generated several rutaecarpine analogs that were subjected to in vitro evaluations. Among these derivatives, RU-75 and RU-184 displayed remarkable inhibitory activity when tested in the 3CL protease assay, S-protein-based ELISA, and pseudovirus entry assay (for both wild-type and omicron variants), and they attenuated the inflammatory response induced by SARS-CoV-2. Interestingly, RU-75 and RU-184 both appeared to be more potent than rutaecarpine itself, and this suggests that they might be considered as lead candidates for future pharmacological elaboration.

Keywords: SARS-CoV-2; computational docking; drug design; rutaecarpine; structure-activity-relationship study; viral entry.

MeSH terms

  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • COVID-19 Drug Treatment
  • Coronavirus 3C Proteases / antagonists & inhibitors
  • Coronavirus 3C Proteases / chemistry
  • Coronavirus 3C Proteases / metabolism
  • Drug Design*
  • Humans
  • Indole Alkaloids* / chemistry
  • Indole Alkaloids* / pharmacology
  • Molecular Docking Simulation*
  • Quinazolines* / chemistry
  • Quinazolines* / pharmacology
  • Quinazolinones
  • SARS-CoV-2* / drug effects
  • Structure-Activity Relationship
  • Virus Internalization / drug effects

Substances

  • rutecarpine
  • Indole Alkaloids
  • Quinazolines
  • Antiviral Agents
  • Coronavirus 3C Proteases
  • Quinazolinones