Identification of a Quinolone-Based Scaffold as a Dual SARS-COV-2 PLᵖʳᵒ and Mᵖʳᵒ Inhibitor: An Integrated Molecular...

Area of Science:

• Drug Discovery
• Computational Chemistry
• Virology

Background:

• The SARS-CoV-2 papain-like protease (PLpro) is crucial for viral replication and immune evasion, making it a key target for antiviral drug development.
• Identifying novel inhibitors of PLpro is essential for developing effective treatments against SARS-CoV-2.

Purpose of the Study:

• To identify novel inhibitors of the SARS-CoV-2 papain-like protease (PLpro) using a multi-faceted virtual screening approach.
• To evaluate the inhibitory potential and characterize the binding interactions of identified compounds against PLpro.

Main Methods:

• Employed a virtual screening strategy integrating pharmacophore modeling, molecular docking, enzymatic assays, and molecular dynamics (MD) simulations.
• Selected 30 top-ranked candidates for experimental enzymatic evaluation.
• Conducted 2D similarity searches to explore structure-activity relationships and synthesized derivatives for further testing.

Main Results:

• A quinolone-based compound, ST50940260, exhibited significant PLpro inhibitory activity (IC50 = 69.53 ± 4.4 µM) and favorable lead-like properties.
• ST50940260 also demonstrated inhibitory activity against the main protease (Mpro) (IC50 = 96.7 µM), suggesting dual-target potential.
• MD simulations and binding free energy calculations confirmed stable complex formation and favorable binding affinities for ST50940260 and its derivative Z30231927.

Conclusions:

• ST50940260 is a promising lead compound for SARS-CoV-2 antiviral drug development, with potential for dual inhibition of PLpro and Mpro.
• Further optimization of ST50940260 and its analogues could lead to potent therapeutic agents.
• The study validates the integrated virtual screening approach for identifying novel antiviral drug candidates.