Upgrading nirmatrelvir to inhibit SARS-CoV-2 Mpro via DeepFrag and free energy calculations

The first oral drug for the treatment of COVID-19, Paxlovid, has been authorized; however, nirmatrelvir, a major component of the drug, is reported to be associated with some side effects. Moreover, the appearance of many novel variants raises concerns about drug resistance, and designing new potent inhibitors to prevent viral replication is thus urgent. In this context, using a hybrid approach combining machine learning (ML) and free energy simulations, 6 compounds obtained by modifying nirmatrelvir were proposed to bind strongly to SARS-CoV-2 Mpro. The structural modification of nirmatrelvir significantly enhances the electrostatic interaction free energy between the protein and ligand and slightly decreases the vdW term. However, the vdW term is the most important factor in controlling the ligand-binding affinity. In addition, the modified nirmatrelvir might be less toxic to the human body than the original inhibitor.

 

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It is interesting to note that the first oral drug for the treatment of COVID-19, Paxlovid, has been authorized. However, there are reports suggesting that nirmatrelvir, a major component of the drug, is associated with certain side effects. Additionally, the emergence of new variants of the virus has raised concerns about drug resistance, necessitating the design of new potent inhibitors to hinder viral replication.

In this context, a hybrid approach that combines machine learning (ML) and free energy simulations was employed to propose six compounds. These compounds were derived from modifications made to nirmatrelvir with the aim of enhancing their binding affinity to SARS-CoV-2 Mpro. The structural modifications of nirmatrelvir resulted in a significant increase in the electrostatic interaction free energy between the protein and ligand, while the van der Waals (vdW) term slightly decreased. It is worth noting that the vdW term is the most critical factor in determining the ligand-binding affinity.

Furthermore, the modified nirmatrelvir compounds may have a lower toxicity profile in the human body compared to the original inhibitor. This suggests that the structural modifications not only improved the binding affinity but also potentially addressed some of the safety concerns associated with nirmatrelvir.

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Related Products

Cat.No.	Product Name	Information
S9866	Nirmatrelvir (PF-07321332)	Nirmatrelvir (PF-07321332) is an reversible covalent inhibitor of SARS-CoV-2 main protease (Mpro, also referred to as 3CL protease) with an ki of 3.11 nM. PF-07321332 binds directly to the catalytic cysteine (Cys145) residue of the enzyme.

Related Targets

SARS-CoV COVID-19