Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation
Bruna K. P. Sousa, Melina Mottin, Donald Seanego, Christopher D. Jurisch, Beatriz S. A. Rodrigues, Verônica L. S. da Silva, Milene Aparecida Andrade, Gilberto Santos Morais-Junior, Diogo F. Boerin, Thamires Quadros Froes, Flávia Nader Motta, Maria Cristina Nonato, Izabela Marques Dourado Bastos, Kelly Chibale, Richard K. Gessner, Carolina Horta Andrade · ACS Medicinal Chemistry Letters · 2024
High Resolution Image Download MS PowerPoint Slide The SARS-CoV-2 pandemic has significantly challenged global public health, highlighting the need for effective therapeutic options. This study focuses on the papain-like protease (PLpro) of SARS-CoV-2, which is a critical enzyme for viral polyprotein processing, maturation, and immune evasion. We employed a combined approach that began with computational models in a virtual screening campaign, prioritizing compounds from our in-house chemical library against PLpro. Out of 81 virtual hits evaluated through enzymatic and biophysical assays, we identified a modest inhibitor featuring a naphthyridine core with an IC 50 of 73.61 μM and a K i of 22 μM. Expanding our exploration, we synthesized and assessed 30 naphthyridine analogues, three of which emerged as promising noncovalent, nonpeptidomimetic inhibitors with IC 50 values between 15.06 and 51.81 μM. Furthermore, in vitro ADMET assays revealed these compounds to possess moderate aqueous solubility, low cytotoxicity, and high microsomal stability, making them excellent candidates for further development targeting SARS-CoV-2 PLpro.