Naringenin-4'-glucuronide as a new drug candidate against the COVID-19 Omicron variant: a study based on molecular docking, molecular dynamics, MM/PBSA and MM/GBSA

Abstract

This study aimed to identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) receptor binding domain (RBD) of the COVID-19 Omicron variant using computer simulations (in silico). NBCs with previously proven biological in vitro activity were obtained from the ZINC database and analyzed through virtual screening, molecular docking, molecular dynamics (MD), molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA), and molecular mechanics/generalized Born surface area (MM/GBSA). Remdesivir was used as a reference drug in docking and MD calculations. A total of 170,906 compounds were analyzed. Molecular docking screening revealed the top four NBCs with a high affinity with the spike (affinity energy <-7 kcal/mol) to be ZINC000045789238, ZINC000004098448, ZINC000008662732, and ZINC000003995616. In the MD analysis, the four ligands formed a complex with the highest dynamic equilibrium S1 (mean RMSD <0.3 nm), lowest fluctuation of the complex amino acid residues (RMSF <1.3), and solvent accessibility stability. However, the ZINC000045789238-spike complex (naringenin-4'-O glucuronide) was the only one that simultaneously had minus signal (-) MM/PBSA and MM/GBSA binding free energy values (-3.74 kcal/mol and −15.65 kcal/mol, respectively), indicating favorable binding. This ligand (naringenin-4'-O glucuronide) was also the one that produced the highest number of hydrogen bonds in the entire dynamic period (average = 4601 bonds per nanosecond). Six mutant amino acid residues formed these hydrogen bonds from the RBD region of S1 in the Omicron variant: Asn417, Ser494, Ser496, Arg403, Arg408, and His505. Naringenin-4'-O-glucuronide showed promising results as a potential drug candidate against COVID-19. In vitro and preclinical studies are needed to confirm these findings.

Communicated by Ramaswamy H. Sarma

Keywords:

• Naringenin-4'-glucuronide
• SARS-CoV-2
• treatment
• spike protein
• in silico

Acknowledgments

The authors express their gratitude to the Brazilian National Council of Technological and Scientific Development (CNPq) and CAPES (Brazilian Federal Agency for Support and Evaluation of Graduate Education within the Ministry of Education of Brazil) for research funding – Finance Code 001

Authors’ contributions

Study concepts: AFC, RP, FST, MMN. Study design: AFC, FST, RP, DPS, MMN, EBM. Data acquisition: AFC, MMN, MMF. Statistical analysis: AFC, MMN, MMF.

Manuscript preparation: AFC, RP, FST, LMF. Manuscript editing: AFC, RP, EBM, FST, LMF. Manuscript review: AFC, RP, EBM, FST, LMF, MMF.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.