Computational Studies on the Structures, Properties, and Pharmacodynamic Characteristics of Nirmatrelvir, its Analogs, and Related Compounds in Synthetic Pathways

Introduction: The early COVID-19 pandemic underscored the urgent need for safe, effective antivirals. Methods: Thirty-three Nirmatrelvir analogs were computationally screened using DFT-based geometry optimization, IR/NMR/UV-Vis/ECD spectral simulation (with solvent effects), conceptual DFT reactivity analysis, drug-likeness assessment, and molecular docking against SARS-CoV-2 Mpro. Results: The data showed consistent structural stability across solvents; electrostatic potential maps revealed key polar regions near the 2-pyrrolidinone/amide oxygens and hydrogens; seven compounds exhibited balanced stability and reactivity; nine showed Nirmatrelvir-like pharmacodynamic profiles; among them, N3-SR4 stood out for its synthetic feasibility, favorable molecular descriptors, and strong Mpro binding affinity. Discussion: The electronic structure, reactivity indices, pharmacokinetic parameters, and molecular docking results all indicate that the synthesized intermediates exhibit a high degree of similarity to the target compounds in key physicochemical and biological activity characteristics. Conclusion: These findings support N3-SR4 as a promising candidate for further experimental validation.