Docking and virtual screening to identify PKC agonists: potentials in anticancer therapeutics

Area of Science:

• Molecular Biology
• Biochemistry
• Pharmacology

Background:

• Protein Kinase C (PKC) activation is crucial in cell signaling pathways initiated by G-protein coupled or tyrosine kinase receptors.
• The PKC C1 domain binds 1,2-diacyl-glycerol (DAG) or other agonists, and its hydrophobic modification upon activation facilitates membrane penetration.
• Phorbol esters, potent PKC agonists, utilize this mechanism to induce tumor formation, highlighting PKC as a therapeutic target.

Purpose of the Study:

• To identify novel heterocyclic compounds that act as potent agonists for Protein Kinase C (PKC).
• To evaluate the potential of these compounds as anti-cancer agents by assessing their ability to inhibit PMA-induced tumor formation and their toxicity profiles.
• To explore existing drugs with similar structures for potential therapeutic applications.

Main Methods:

• Virtual docking of 300 heterocyclic compounds, structurally similar to phorbol 12-myristate 13-acetate (PMA), against the PKC-α C1 domain.
• Agonist competition assays to identify potent PKC agonists that bind more effectively than PMA.
• In silico toxicity analysis to assess the non-toxic, non-mutagenic, and non-tumorigenic potential of the identified compounds.

Main Results:

• Five heterocyclic compounds (Zc 67913417, Zc 68601770, Zc 25726447, Zc 35376386, Zc 49785214) were identified as potent PKC agonists with superior binding energy and interactions compared to PMA.
• The identified compounds effectively abolished the carcinogenic effects of PMA.
• Testing of two approved drugs, nandrolone decanoate and budesonide, showed dose-dependent reduction in cellular viability with nanomolar IC50 values.
• In silico analysis confirmed the non-toxic, non-mutagenic, and non-tumorigenic nature of the top hit molecules.

Conclusions:

• Virtual screening and experimental validation successfully identified five novel, potent PKC agonists with potential anti-cancer properties.
• These compounds exhibit favorable binding characteristics and effectively counteract PMA's carcinogenic effects.
• The identified molecules represent promising candidates for future drug discovery and development in oncology, with some approved drugs showing therapeutic potential.