Study on the interaction of polyamine transport (PAT) and 4-Chloro-naphthalimide-homospermidine conjugate (4-ClNAHSPD) by molecular docking and dynamics

Abstract

Polyamine transporter (PAT) is a protein that can deliver "drug-polyamine" conjugates to tumor cells. 4-Chloro-naphthalimide- homospermidine (4-ClNAHSPD) displayed good antitumor activity and excellent cell selectivity via PAT pathway. In this paper, 4-ClNAHSPD and spermidine (SPD) were docked against PAT. The results showed that 4-ClNAHSPD could bind to PAT through hydrogen bond, Van der Waals, salt bridge or attractive charge and hydrophobic interaction. The interaction of SPD and PAT, however, was hydrogen bond and Van der Waals interaction. Moreover, their binding sites were also different. The primary binding sites of 4-ClNAHSPD with PAT are the residues of VAL59, HIS222, ASP61, ASP179 and GLU64, while SPD interacts with PAT in the sites of ASP37, ASP244, APS275 and SER36. The docked ligand-protein complexes were simulated for 5000ps. In simulations, various binding sites further resulted in the diverse root-mean-square deviation (RMSD) and root-mean-square deviation fluctuation (RMSF) values. The RMSD and RMSF values of 4-ClNAHSPD-PAT indicated that 4-ClNAHSPD caused a weak conformational change of PAT in a different style from SPD. More importantly, the interaction force numbers of 4-ClNAHSPD-PAT were also changed after the simulation. These results supported that 4-ClNAHSPD harnesses PAT pathway for cellular entrance.

Communicated by Ramaswamy H. Sarma

Keywords:

• 4-ClNAHSPD
• PAT
• molecular docking
• dynamics

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Henan Programs for Science and Technology Development (No. 182102310119) and the Natural Science Foundation of Education (No 18A350001). We wish to thank the Super Computer Center of Henan for providing us the Discovery Studio 2017R2 software for the virtual docking and simulation work.