Exploring New Small Molecule Inhibitors for SARS‐CoV‐2 3CLpro: A Comprehensive Computational Study

The SARS‐CoV‐2 3C‐like protease (3CLpro) has emerged as a key target for drug development owing to its crucial role in viral replication of SARS‐CoV‐2 virus. In this study, we employed a ligand‐based virtual screening strategy to identify potential small molecules capable of binding to SARS‐CoV‐2 3CLpro. Using GC376 as a reference compound, we conducted a comprehensive search in a chemical database and identified 178 candidate molecules (CPLs) with structural similarity to GC376. Molecular docking analyses revealed that several CPLs exhibited superior binding affinities to SARS‐CoV‐2 3CLpro compared to GC376. Notably, CPL‐390, CPL‐374, and CPL‐306 displayed the highest binding energies, indicating their potential as inhibitors of SARS‐CoV‐2 3CLpro. Detailed analysis of noncovalent interactions and molecular mechanics generalized Born surface area (MMGBSA) calculations further supported the binding affinity of CPLs to SARS‐CoV‐2 3CLpro. Key interactions with catalytic residues and steric hindrance within the binding pocket highlighted potential inhibition mechanisms for CPL‐306, CPL‐374, and CPL‐390. Moreover, pharmacokinetic analysis indicated that CPL‐306, CPL‐374, and CPL‐390 possessed favorable absorption, distribution, metabolism, and excretion (ADME) properties, positioning them as promising candidates for further drug development. In contrast, GC376 exhibited less favorable pharmacological characteristics, emphasizing the need for novel compounds with improved profiles. SARS‐CoV‐2 3CLpro is a key target for COVID‐19 treatment. Using GC376 as a base, CPL‐390, CPL‐374, and CPL‐306 exhibited stronger binding and stability in molecular docking, molecular dynamics simulation, and MMBGSA analyses, with promising pharmacokinetics.