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Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro

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Structure-Informed Design of High-Cooperativity PROTAC Targeting SARS-CoV-2 RdRp via Click Chemistry and Enhanced

Kiran Shehzadi¹, Yue Ran¹, Iqra Kalsoom¹

¹School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 10081, China.

Journal of Medicinal Chemistry

|November 5, 2025

Summary

We designed novel Proteolysis-Targeting Chimeras (PROTACs) to degrade SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). PROTAC 10 demonstrated potent antiviral activity by stabilizing the ternary complex and enhancing protein degradation.

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Area of Science:

Molecular Biology
Drug Discovery
Virology

Background:

Targeted protein degradation using Proteolysis-Targeting Chimeras (PROTACs) shows potential for antiviral therapies.
Inefficient ternary complex formation is a key challenge in developing effective PROTACs.

Purpose of the Study:

To design novel PROTACs targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) for antiviral therapy.
To optimize PROTACs for enhanced ternary complex formation and viral protein degradation.

Main Methods:

De novo design and screening of 600 PROTAC candidates.
Utilizing repurposed antiviral scaffolds and optimizing E3 ligase ligands.
Synthesis via modular click chemistry (CuAAC) and molecular dynamics simulations.

Main Results:

Identification of PROTAC 10, a molnupiravir-CRBN conjugate, with high-affinity binding (Kd = 1.09 nM) and positive cooperativity (α = 45.9).
Effective CRBN-mediated RdRp degradation (DC50 = 1.97 μM) and potent antiviral activity (IC50 = 3.12 μM) in infected cells.
Engineered linker enhanced ternary complex stability (ΔGTER = -247 kcal/mol) and cooperativity.

Conclusions:

PROTAC 10 represents a promising antiviral agent targeting SARS-CoV-2 RdRp.
Rational linker optimization is a viable strategy for designing effective antiviral PROTACs.
This framework enables selective viral protein degradation for therapeutic development.