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Novel Competitive, Nonpeptidic, SARS-CoV‑2 Mpro Inhibitors with Improved Solubility.
Zafer Sahin1, Mario Rivera1, Yanli Yang1
1Department of Chemistry, Emory University College of Arts and Sciences, Atlanta, Georgia 30322, United States.
ACS Medicinal Chemistry Letters
|May 20, 2026
Summary
Researchers aimed to enhance SARS-CoV-2 protease inhibitors for better solubility and stability. Disrupting aromatic ring coplanarity improved solubility but reduced potency, necessitating further optimization for effective antiviral drug development.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Computational Chemistry
Background:
- Previous work identified novel, nonpeptidic competitive inhibitors for the SARS-CoV-2 main protease.
- Improving water solubility and metabolic stability are crucial for developing effective antiviral therapeutics.
Purpose of the Study:
- To enhance the physicochemical properties (water solubility, metabolic stability) of previously identified SARS-CoV-2 main protease inhibitors.
- To investigate structure-activity relationships concerning aromatic ring arrangements and pocket occupancies (S1, S4) for potency and stability.
Main Methods:
- Free energy perturbation (FEP+) calculations were employed to predict solubility changes.
- Chemical modifications were designed to disrupt aromatic ring coplanarity and alter interactions within protease binding pockets.
- In vitro assays were used to evaluate compound potency and metabolic stability.
Main Results:
- Disrupting the coplanar arrangement of aromatic rings significantly improved aqueous solubility, as predicted by FEP+ studies.
- This structural modification, however, resulted in an unacceptable loss of inhibitory potency.
- Modifications aimed at improving metabolic stability by altering S4 pocket interactions and retaining potency via S1 pocket pyridyl ring changes were explored.
Conclusions:
- While improved water solubility was achieved, the loss in potency highlights a critical challenge in optimizing these nonpeptidic inhibitors.
- Further medicinal chemistry efforts are required to balance solubility, metabolic stability, and potency for developing viable SARS-CoV-2 protease inhibitors.
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