Identification of high-affinity pyridoxal kinase inhibitors targeting cancer therapy: an integrated docking and...

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Pyridoxal kinase (PDXK) is a vitamin B6-dependent enzyme vital for leukemic cell proliferation.
• Overexpression of PDXK and pyridoxal 5'-phosphate (PLP) in carcinomas suggests their potential as cancer drug targets.
• Targeting PDXK offers a promising therapeutic strategy for cancer treatment.

Purpose of the Study:

• To discover novel inhibitors that selectively block pyridoxal phosphate (PLP) binding to pyridoxal kinase (PDXK).
• To evaluate the stability and structural impact of potential PDXK inhibitors using molecular dynamics simulations.

Main Methods:

• Virtual screening of a large compound library (728,747 compounds) using molecular docking against the PDXK substrate binding pocket.
• All-atom molecular dynamics simulations (100 ns) of PDXK-ligand complexes to assess binding stability.
• Identification of critical residues involved in PDXK-PLP complex formation.

Main Results:

• Six promising compounds (ZINC095099376, ZINC01612996, ZINC049841390, ZINC095098959, ZINC01482077, ZINC03830976) were identified as potential PDXK inhibitors.
• Molecular dynamics simulations confirmed that these ligands induced minor structural changes and stabilized the PDXK structure.
• The study elucidated key residues crucial for PDXK-PLP interactions.

Conclusions:

• The identified compounds demonstrate potential as anticancer agents by inhibiting PDXK.
• These findings provide a foundation for designing specific and effective PDXK inhibitors for cancer therapy.
• Further studies are warranted to develop these compounds as potential anticancer drugs targeting PDXK.