2. Academic Validation
  3. Novel Competitive, Nonpeptidic, SARS-CoV‑2 Mpro Inhibitors with Improved Solubility

Novel Competitive, Nonpeptidic, SARS-CoV‑2 Mpro Inhibitors with Improved Solubility

  • ACS Med Chem Lett. 2026 May 6;17(5):1132-1137. doi: 10.1021/acsmedchemlett.6c00041.
Zafer Sahin 1,  Mario Rivera 1,  Yanli Yang 1,  Ken Liu 1,  Goknil P C Sahin 2,  John Bacsa 1,  Stephen C Pelly 1,  Dennis C Liotta 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Emory University College of Arts and Sciences, Atlanta, Georgia 30322, United States.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University, 34752 Istan-bul, Türkiye.
PMID: 42157831 DOI: 10.1021/acsmedchemlett.6c00041
Abstract

In continuation of our previous work wherein we described novel, nonpeptidic competitive inhibitors of the SARS-CoV-2 main protease, we here describe our efforts to improve upon these compounds by improving water solubility and metabolic stability. As predicted by FEP+ solubility studies, disrupting the coplanar arrangement of the aromatic rings led to significantly improved compound aqueous solubility, unfortunately with an unacceptable loss in potency. Attempts to improve compound metabolic stability by avoiding aromatic moieties occupying the S4 pocket, while retaining compound potency by modification of the pyridyl ring occupying the S1 pocket, were also investigated.

Keywords

COVID-19; FEP+; SARS-CoV-2; main protease.

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