Structure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Main Protease

TLDR

The SARS‑CoV main protease is essential for viral maturation and is therefore a prime target for structure‑based antiviral drug design. Using structure‑based virtual screening of 58,855 compounds, the authors identified two hit scaffolds, generated 21 analogues, and solved crystal structures of the most potent inhibitors bound to Mpro. The analogues displayed IC50 values below 50 µM, with the best compound at 0.3 µM, binding non‑covalently through extensive H‑bond and hydrophobic interactions, inducing conformational changes that disrupt the catalytic dyad.

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (Mpro), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58 855 compounds followed by the testing of potential compounds for SARS-CoV Mpro inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search. Twenty-one analogues derived from these two hits exhibited IC50 values below 50 μM, with the most potent one showing 0.3 μM. Furthermore, the complex structures of two potent inhibitors with SARS-CoV Mpro were solved by X-ray crystallography. They bind to the protein in a distinct manner compared to all published SARS-CoV Mpro complex structures. They inhibit SARS-CoV Mpro activity via intensive H-bond network and hydrophobic interactions, without the formation of a covalent bond. Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms, particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.