Identification of high-affinity pyridoxal kinase inhibitors targeting cancer therapy: an integrated docking and molecular dynamics simulation approach

Abstract

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

Keywords:

• Pyridoxal kinase
• molecular docking
• molecular dynamics simulation
• DFT calculation
• specific inhibitors
• cancer therapy

Acknowledgments

We are thankful to Bioinformatics Resources and Applications Facility (BRAF), CDAC, Pune. MIH thanks to the Indian Council of Medical Research (Grant No. 45/6/2020-DDI/BMS) and (ISRM/12(22)/2020). AC acknowledges the Department of Health Research (DHR), New Delhi for the award of YS fellowship [R.12014/30/2022].

Author’s contributions

IQ designed and conceptualized the project; PB and AC carried out virtual screening, docking studies, molecular dynamics simulation and other computational analysis; PB wrote the manuscript; TM, MIH and NS edited the manuscript and figures. All the authors reviewed and approved the final version of the manuscript.

Disclosure statement

The authors report no conflicts of interest with the content of this article.

Additional information

Funding

This work was funded and supported by the Indian Council of Medical Research (Grant No. BIC/12(05)/2015).