Computational Studies on the Structures, Properties, and Pharmacodynamic Characteristics of Nirmatrelvir, its Analogs, and Related Compounds in Synthetic Pathways
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Updated: Apr 21, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Qiang Dai1, Yanni Wang2, Hong Li2
1The Oncology Chemotherapy Department of Ruian People's Hospital, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325200, Zhejiang, China.
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.
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