The RGD tripeptide anticancer drug carrier: DFT computations and molecular dynamics simulations

Abstract

The density functional theory (DFT) computations at B3LYP/6-31+G(d,p) level of theory was accomplished in water solvent to investigate the properties of twenty drug delivery systems formed between the tripeptide arginyl-glycyl-aspartic acid (RGD) carrier and the commercially well-known cyclophosphamide (CP) anticancer drug. The CP-RGD-7 produced by the hydrogen bond between phosphoryl (PO) oxygen atom of cyclophosphamide and OH hydrogen atom of RGD had the most negative binding energy. The dipole moments of CP and RGD were close to 8 Debye and this value was increased to 11.403, 7.5398, 14.946 and 10.321 in structures 1, 6, 7 and 8, respectively, demonstrating water (1.85 Debye) with high polarity and non-toxicity, is an appropriate solvent for delivery of such polar CP-RGD systems. The HOMO orbital in all CP-RGD systems was positioned on the cyclophosphamide but the LUMO orbital was dispersed on the tripeptide. Between CP-RGD-7 and CP-RGD-8 having the least binding energy values, CP-RGD-8 exhibited smaller values of chemical potential, energy gap and hardness but the greatest electronegativity and electrophilicity index that certified this structure had greater affinity for binding onto the cancerous tissue. Accordingly, it was established that among all CP-RGD systems, the CP-RGD-8 was the most promising system for the cancer treatment. Considering the molecular dynamics (MD) simulations results obtained at two temperatures (25 and 37 °C), the CP-3RGD was chosen as the most suitable system due to it exhibited desirable drug loading capacity and slow release rate.