Macrolactin A as a Novel Inhibitory Agent for SARS-CoV-2 M^pro: Bioinformatics Approach.

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• The global COVID-19 pandemic necessitates the urgent search for effective therapeutic agents.
• Natural bioactive compounds offer a promising avenue for drug discovery against SARS-CoV-2.
• Inhibiting the SARS-CoV-2 main protease (Mpro) is a key strategy for antiviral therapy.

Purpose of the Study:

• To identify natural bioactive compounds with potential to inhibit SARS-CoV-2 Mpro using in silico screening.
• To evaluate the drug-likeness, antiviral activity, and binding affinity of selected compounds.
• To assess the stability and binding energy of top candidate compounds through molecular dynamics simulations.

Main Methods:

• In silico screening including drug likeliness, antiviral activity prediction, molecular docking, ADME analysis, molecular dynamics (MD) simulation, and MM/GBSA calculations.
• Utilized SARS-CoV-2 Mpro crystal structure (PDB: 6LU7) for molecular docking studies.
• Shortlisted compounds based on Lipinski's rule and predicted antiviral activity.

Main Results:

• 17 compounds met Lipinski's rule criteria, with 5 showing significant predicted antiviral activity.
• Macrolactin A and Stachyflin exhibited strong binding energies (-9.22 and -8.00 kcal/mol) to Mpro catalytic residues.
• MD simulations and MM/GBSA calculations confirmed the stability and high binding free energy of the Mpro-Macrolactin A complex (-42.58 ± 6.35 kcal/mol).

Conclusions:

• Marine natural compound Macrolactin A is a potential therapeutic inhibitor of SARS-CoV-2 Mpro.
• Macrolactin A demonstrates favorable in silico properties for drug development against COVID-19.
• Further in vitro and in vivo studies are essential to validate Macrolactin A's efficacy and determine therapeutic dosage.