2. Academic Validation
  3. Pocket-Based Generative Diffusion Model Accelerates Potent Influenza A Hemagglutinin Inhibitor Discovery

Pocket-Based Generative Diffusion Model Accelerates Potent Influenza A Hemagglutinin Inhibitor Discovery

  • J Med Chem. 2026 Feb 26;69(4):4969-4983. doi: 10.1021/acs.jmedchem.5c03787.
Wenrui Gai 1,  Shuang Wu 1,  Bohan Li 1,  Yang Zhang 1 2,  Zihan Wang 1,  Yueling Teng 1,  Guangyuan Luo 1,  Zhengjie Wang 1,  Qi Wang 1,  Wanting Jiao 3,  Qian Che 1,  Guojian Zhang 1 2 4,  Tianjiao Zhu 1,  Wei Wang 1 2,  Dehai Li 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs Ministry of Education, School of Medicine and Pharmacy, Sanya Oceanographic Institute, Frontiers Science Center for Deep Ocean Multispheres and Earth System, Ocean University of China, Qingdao 266003, People's Republic of China.
  • 2 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, People's Republic of China.
  • 3 Ferrier Research Institute, Victoria University of Wellington, Wellington 6012, New Zealand.
  • 4 Marine Biomedical Research Institute of Qingdao, Qingdao 266071, People's Republic of China.
PMID: 41685832 DOI: 10.1021/acs.jmedchem.5c03787
Abstract

The deep generative model has recently advanced 3D chemical space exploration but overlooked the balance between target affinity and structural rationality, limiting their effectiveness in drug discovery. Herein, we established a novel dual conditional diffusion model (DCDM) that leveraged ligand-protein interaction features to refine 3D target-based molecular generation. DCDM exhibited superiority in enhancing predicted binding affinity while maintaining high structural rationality and diversity. Subsequently, we applied DCDM to optimize penindolone (PND), a marine-derived lead compound from our laboratory, targeting influenza A hemagglutinin (HA). Efficiently, a promising candidate (compound C2e) was successfully obtained from eight synthesized derivatives inspired by the DCDM-generated molecules, with a 26-fold higher affinity for HA. Notably, C2e exhibited a 10-fold decrease in IC50 compared with the parent compound PND. Further in vivo assessments demonstrated its potent Antiviral activity and safety. All results indicate that DCDM is a valuable generative model, capable of accelerating drug development in real-world applications.

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