Identification of high-affinity pyridoxal kinase inhibitors targeting cancer therapy: an integrated docking and molecular dynamics simulation approach.
Pallabi BanerjeeAnshuman ChandraTaj MohammadNagendra SinghM D Imtaiyaz HassanImteyaz QamarPublished in: Journal of biomolecular structure & dynamics (2023)
Pyridoxal kinase (PDXK) is a vitamin B6-dependent transferase enzyme encoded by the PDXK gene, crucial for leukemic cell proliferation. Disruption of its activity causes altered metabolism and reduced levels of nucleotides and polyamines. PDXK and pyridoxal 5'-phosphate (PLP) are overexpressed in various carcinomas, making them promising targets for drug design against cancer. Targeting PDXK may hold promise as a therapeutic approach for cancer treatment. This study focused on discovering potential inhibitors that could selectively interrupt the binding of pyridoxal phosphate (PLP) to pyridoxal kinase (PDXK). A commercially available library of 7,28,747 natural and druglike compounds was virtually screened using a molecular docking approach to target the substrate binding pocket of PDXK. Six promising inhibitors were identified, and all-atom molecular dynamics simulations were conducted on the PDXK-ligand complexes for 100 ns to assess their binding conformational stability. The simulation results indicated that the binding of ZINC095099376, ZINC01612996, ZINC049841390, ZINC095098959, ZINC01482077, and ZINC03830976 induced a slight structural change and stabilized the PDXK structure. This analysis provided valuable information about the critical residues involved in the PDXK-PLP complex formation and can be utilized in designing specific and effective PDXK inhibitors. According to this study, these compounds could be developed as anticancer agents targeting PDXK as a potential candidate for further study.Communicated by Ramaswamy H. Sarma.
Keyphrases
- molecular dynamics simulations
- molecular docking
- cancer therapy
- oxide nanoparticles
- cell proliferation
- molecular dynamics
- drug delivery
- acute myeloid leukemia
- squamous cell carcinoma
- binding protein
- emergency department
- health information
- dna binding
- copy number
- dengue virus
- tyrosine kinase
- big data
- papillary thyroid
- cell cycle
- adverse drug
- stress induced
- protein protein
- lymph node metastasis
- aedes aegypti
- squamous cell