Tripeptide arginyl-glycyl-aspartic acid (RGD) for delivery of Cyclophosphamide anticancer drug: A computational approach

Density functional theory (DFT) calculations were performed on tripeptide arginyl-glycyl-aspartic acid (RGD) as an efficient drug carrier to deliver the commercially famous cyclophosphamide (CP) anticancer drug within ethanol solution. The most negative binding energy (-5.22 kcal/mol) was measured for the CP-RGD-7 created through the H-bond interaction between the P=O (phosphoryl) oxygen atom of the CP and hydrogen atom of O-H group in the RGD. The quantum theory of atoms in molecules (QTAIM) proved that the CP-RGD-6 was composed of five intra-molecular CH…HC, N…HC and NH…OC plus one inter-molecular NH…N interactions. Among CP-RGD-6, CP-RGD-7 and CP-RGD-8 with the smallest binding energies (highest structural stabilities), the CP-RGD-6 showed the minimum hardness, energy gap and chemical potential whereas the utmost electrophilicity index and electronegativity which confirmed it could the most effectively be bound onto the cancer cells. Consequently, among twenty designed carriers, the CP-RGD-6 was recognized as the most promising drug delivery system. According to the results achieved from the molecular dynamics (MD) simulations performed in ethanol solvent on the CP-RGD-PEG systems containing different number of PEG chains, it was established that the CP-RGD-6PEG cell was the most suitable vehicle with desirable FV (4988.89 Å3) and FFV (22.66%) values as well as small drug diffusion coefficient (0.0114×10–5 cm2/s) indicating low drug release rate.