Journal
BIOLOGY-BASEL
Volume 10, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/biology10080789
Keywords
COVID-19; SARS-CoV-2; main protease; Leucas zeylanica; GC-MS; molecular dynamics simulation
Categories
Funding
- Taif University Researchers Supporting Project Taif, Saudi Arabia [TURSP-2020/163]
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The study utilized molecular docking and molecular dynamics simulation to identify potential inhibitors from Leucas zeylanica for the main protease of SARS-CoV-2. The identified phytochemicals showed toxicity but stable binding affinity, demonstrating potential as antiviral drug candidates. Through computational drug design, three compounds were identified with high docking scores and interactions with key amino acids in the SARS-CoV-2 main protease catalytic groove, suggesting their potential in combating the virus.
Simple Summary Molecular docking in conjunction with molecular dynamics simulation was accomplished as they extend an ample opportunity to screen plausible inhibitors of the main protease from Leucas zeylanica. The preferential phytochemicals were identified from L. zeylanica through gas chromatography-mass spectrometry (GC-MS). The pre-eminent three identified phytochemicals exhibited toxicity by no means during the scrutinization of ADME/T prominences. Moreover, pharmacologically distinguishing characteristics and the biological activity of the lead phytochemicals were satisfying as an antiviral drug contender. Additionally, the molecular dynamics simulation exhibited thermal stability and a stable binding affinity of the protein-compound complex that referred to the appreciable efficacy of lead optimization. Therefore, the preferable phytochemicals are worth substantial evaluation in the biological laboratory to recommend plausible antiviral drug candidates. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a contemporary coronavirus, has impacted global economic activity and has a high transmission rate. As a result of the virus's severe medical effects, developing effective vaccinations is vital. Plant-derived metabolites have been discovered as potential SARS-CoV-2 inhibitors. The SARS-CoV-2 main protease (M-pro) is a target for therapeutic research because of its highly conserved protein sequence. Gas chromatography-mass spectrometry (GC-MS) and molecular docking were used to screen 34 compounds identified from Leucas zeylanica for potential inhibitory activity against the SARS-CoV-2 M-pro. In addition, prime molecular mechanics-generalized Born surface area (MM-GBSA) was used to screen the compound dataset using a molecular dynamics simulation. From molecular docking analysis, 26 compounds were capable of interaction with the SARS-CoV-2 M-pro, while three compounds, namely 11-oxa-dispiro[4.0.4.1]undecan-1-ol (-5.755 kcal/mol), azetidin-2-one 3,3-dimethyl-4-(1-aminoethyl) (-5.39 kcal/mol), and lorazepam, 2TMS derivative (-5.246 kcal/mol), exhibited the highest docking scores. These three ligands were assessed by MM-GBSA, which revealed that they bind with the necessary M-pro amino acids in the catalytic groove to cause protein inhibition, including Ser144, Cys145, and His41. The molecular dynamics simulation confirmed the complex rigidity and stability of the docked ligand-M-pro complexes based on the analysis of mean radical variations, root-mean-square fluctuations, solvent-accessible surface area, radius of gyration, and hydrogen bond formation. The study of the postmolecular dynamics confirmation also confirmed that lorazepam, 11-oxa-dispiro[4.0.4.1]undecan-1-ol, and azetidin-2-one-3, 3-dimethyl-4-(1-aminoethyl) interact with similar M-pro binding pockets. The results of our computerized drug design approach may assist in the fight against SARS-CoV-2.
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