Brussonol and komaroviquinone as inhibitors of the SARS-CoV-2 Omicron BA.2 variant spike protein: A molecular docking, molecular dynamics, and quantum biochemistry approach.

Abstract

Since late 2019, humanity has faced the challenges posed by the COVID-19 pandemic, caused by the SARS-CoV-2 virus. The continuous evolution of SARS-CoV-2 has led to the emergence of multiple Variants of Concern (VOCs) and Variants of Interest (VOIs), posing significant risks to global health. SARS-CoV-2 infects host cells via the angiotensin-converting enzyme 2 (ACE2) receptors, facilitated by the spike (S) protein. Icetexane diterpenes, including brussonol and komaroviquinone, exhibit notable anti-inflammatory, antibacterial, antiviral, antiproliferative, and anticancer properties. Recent research has explored their potential as inhibitors of the SARS-CoV-2 3Clpro protease, showing promising efficacy comparable to Nirmatrelvir. This study investigates brussonol and komaroviquinone as potential inhibitors of the SARS-CoV-2 Omicron BA.2 variant spike protein using molecular docking, molecular dynamics simulations, and quantum biochemistry approaches. The stability and interaction energies of brussonol, komaroviquinone, and mefloquine with the SARS-CoV-2 Omicron BA.2 variant spike protein were evaluated. RMSD analysis demonstrated that komaroviquinone and mefloquine maintain more stable binding poses with the spike protein compared to various NAGs and glycans. Electrostatic potential maps revealed significant interactions with ASN603, a critical residue for ligand binding efficacy. Furthermore, this study addresses a gap in current research, as no studies were found that simulate the trimer of the SARS-CoV-2 BA.2 variant spike protein. Most existing studies focus on the monomer and often exclude the NAGs and glycans. This research underscores the importance of maintaining the NAGs and glycans in the trimer simulations, providing a more accurate representation of the protein's structure and its interactions with ligands. The findings indicate that both komaroviquinone and brussonol exhibit higher binding affinities compared to mefloquine. This study provides valuable insights into the molecular interactions of these compounds, highlighting their potential for further development as antiviral agents against SARS-CoV-2.