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

Document Type: Reasearch Paper


Department of Chemistry, Amirkabir University of Technology (Tehran Polytechnic), P.O.Box:15875-4413, Tehran, Iran.


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.


[1]    Tian B., Liu Y., Liu J., (2020), Cyclodextrin as a magic switch in covalent and non-covalent anticancer drug release systems. Carbohydr. Polym. 242: 116401.

[2]    Ahmadi R., Ebrahimzadeh M. A., (2020), Resveratrol–A comprehensive review of recent advances in anticancer drug design and development. Eur. J. Med. Chem. 200: 112356.

[3]    Adebayo-Tayo B. C., Inem S. A., Olaniyi O. A., (2019), Rapid synthesis and characterization of Gold and Silver nanoparticles using exopolysaccharides and metabolites of Wesiella confusa as an antibacterial agent against Esherichia coli. Int. J. Nano Dimens. 10: 37-47.

[4]    Saadatmand M. M., Yazdanshenas M. E., Khajavi R., Mighani F., Toliyat T., (2019), Patterning the surface roughness of a nano fibrous scaffold for transdermal drug release. Int. J. Nano Dimens. 10: 78-88.

[5]    Verma P., Maheshwari S. K., (2019), Applications of Silver nanoparticles in diverse sectors. Int. J. Nano Dimens. 10: 18-36.

[6]    Ghavidel M., Shirazi Beheshtiha S. Y., Heravi M., (2018), Cu(I) nanoparticles immobilized onto poly(vinylpyridine-N-N-methylenebisacrylamide-acrylicacid) as a new, efficient and recyclable catalyst for the regioselective synthesis of 1, 2, 3-Triazoles via click reaction in water. Int. J. Nano Dimens. 9: 408-420.

[7]    Ahmadi R., Jalali Sarvestani M. R., Sadeghi B., (2018), Computational study of the fullerene effects on the properties of 16 different drugs: A review. Int. J. Nano Dimens. 9: 325-335.

[8]    Mirzaei M., (2013), Effects of carbon nanotubes on properties of the fluorouracil anticancer drug: DFT studies of a CNT-fluorouracil compound. Int. J. Nano Dimens. 3: 175-179.

[9]    Gao F., Sun Z., Kong F., Xiao J., (2020), Artemisinin-derived hybrids and their anticancer activity. Eur. J. Med. Chem. 188: 112044.

[10]  Shariatinia Z., (2019), Pharmaceutical applications of chitosan. Adv. Colloid Interface Sci. 263:131-194.

[11]  Shariatinia Z., (2018), Carboxymethyl chitosan: Properties and biomedical applications. Int. J. Biol. Macromol. 120: 1406-1419.

[12]  Shariatinia Z., Fazli M., (2015), Mechanical properties and antibacterial activities of novel nanobiocomposite films of chitosan and starch. Food Hydrocolloids. 46: 112-124.

[13]  Shariatinia Z., Jalali A. M., (2018), Chitosan-based hydrogels: Preparation, properties and applications. Int. J. Biol. Macromol. 115: 194-220.

[14]  Shariatinia Z., Mazloom-Jalali A., (2019), Chitosan nanocomposite drug delivery systems designed for the ifosfamide anticancer drug using molecular dynamics simulations. J. Mol. Liq. 273: 346-367.

[15]  Mazloom-Jalali A., Shariatinia Z., Tamai I. A., Pakzad S.-R., Malakootikhah J., (2020), Fabrication of chitosan–polyethylene glycol nanocomposite films containing ZIF-8 nanoparticles for application as wound dressing materials. Int. J. Biol. Macromol. 153: 421-432.

[16]  Shariatinia Z., Barzegari A., (2019), Chapter 22-Polysaccharide hydrogel films/membranes for transdermal delivery of therapeutics. In: Polysaccharide Carriers for Drug Delivery. Edited by Maiti S., Jana S., Woodhead Publishing. 639-684.

[17]  Shariatinia Z., Mohammadi-Denyani A., (2018), Advances in polymers for drug delivery and wound healing applications. In: Advances in Polymers for Biomedical Applications. Nova Science Publisher.

[18]  Shariatinia Z., Nikfar Z., Gholivand K., Abolghasemi Tarei S., (2015), Antibacterial activities of novel nanocomposite biofilms of chitosan/phosphoramide/Ag NPs. Polym. Compos. 36: 454-466.

[19]  Shariatinia Z., Zahraee Z., (2017), Controlled release of metformin from chitosan–based nanocomposite films containing mesoporous MCM-41 nanoparticles as novel drug delivery systems. J. Colloid Interface Sci. 501: 60-76.

[20]  Vatanparast M., Shariatinia Z., (2019), Revealing the role of different nitrogen functionalities in the drug delivery performance of graphene quantum dots: A combined density functional theory and molecular dynamics approach. J. Mater. Chem. B. 7: 6156-6171.

[21]  Fazli Y., Shariatinia Z., Kohsari I., Azadmehr A., Pourmortazavi S. M., (2016), A novel chitosan-polyethylene oxide nanofibrous mat designed for controlled co-release of hydrocortisone and imipenem/cilastatin drugs. Int. J. Pharm. 513: 636-647.

[22]  Kohsari I., Shariatinia Z., Pourmortazavi S. M., (2016), Antibacterial electrospun chitosan-polyethylene oxide nanocomposite mats containing ZIF-8 nanoparticles. Int. J. Biol. Macromol. 91: 778-788.

[23]  Kohsari I., Shariatinia Z., Pourmortazavi S. M., (2016), Antibacterial electrospun chitosan–polyethylene oxide nanocomposite mats containing bioactive silver nanoparticles. Carbohydr. Polym. 140: 287-298.

[24]  Fazli Y., Shariatinia Z., (2017), Controlled release of cefazolin sodium antibiotic drug from electrospun chitosan-polyethylene oxide nanofibrous mats. Mater. Sci. Eng. C. 71: 641-652.

[25]  Nikfar Z., Shariatinia Z., (2019), The RGD tripeptide anticancer drug carrier: DFT computations and molecular dynamics simulations. J. Mol. Liq. 281: 565-583.

[26]  Shariatinia Z., (2020), Biopolymeric nanocomposites in drug delivery. In: Advanced Biopolymeric Systems for Drug Delivery. edn. Edited by Nayak A. K., Hasnain M. S. Cham: Springer International Publishing. 233-290.

[27]  Shariatinia Z., (2019), Chapter 2-Pharmaceutical applications of natural polysaccharides. In: Natural Polysaccharides in Drug Delivery and Biomedical Applications. Edited by Hasnain M. S., Nayak A. K., Academic Press. 15-57.

[28]  Shariatinia Z., Fasihozaman-Langroodi K., (2019), Chapter 8-Biodegradable Polymer Nanobiocomposite Packaging Materials. In: Trends in Beverage Packaging. Edited by Grumezescu A. M., Holban A. M., Academic Press. 191-241.

[29]  Kohsari I., Mohammad-Zadeh M., Minaeian S., Rezaee M., Barzegari A., Shariatinia Z., Koudehi M. F., Mirsadeghi S., Pourmortazavi S. M., (2019), In vitro antibacterial property assessment of silver nanoparticles synthesized by Falcaria vulgaris aqueous extract against MDR bacteria. J. Sol-Gel Sci. Techn. 90: 380-389.

[30]  Faramarzi R., Falahati M., Mirzaei M., (2020), Interactions of fluorouracil by CNT and BNNT: DFT Analyses. Adv. J. Sci. Eng. 1: 62-66.

[31]  Mirzaei M., (2013), Formation of a peptide assisted bi-graphene and its properties: DFT studies. Superlatt. Microstruct. 54: 47-53.

[32]  Mirzaei M., Hadipour N. L., (2008), Study of hydrogen bonds in N-methylacetamide by DFT calculations of oxygen, nitrogen, and hydrogen solid-state NMR parameters. Struct. Chem. 19: 225-232.

[33]  Mirzaei M., Meskinfam M., Yousefi M., (2012), Covalent hybridizations of carbon nanotubes through peptide linkages: A density functional approach. Comput. Theor. Chem. 981: 47-51.

[34]  Mirzaei M., Samadi Z., Hadipour N. L., (2010), Hydrogen bonds of peptide group in four acetamide derivatives: DFT study of oxygen and nitrogen NQR and NMR parameters. J. Iranian Chem. Soc. 7: 164-170.

[35]  Xu Y., Zhang X., Wang N., Pei X., Guo Y., Wang J., Barth S., Yu F., Lee S. J., He H., Yang V. C., (2020), Cell-penetrating peptide enhanced insulin buccal absorption. Int. J. Pharm. 584: 119469.

[36]  Kang Z., Ding G., Meng Z., Meng Q., (2019), The rational design of cell-penetrating peptides for application in delivery systems. Peptides. 121: 170149.

[37]  Xu J., Khan A. R., Fu M., Wang R., Ji J., Zhai G., (2019), Cell-penetrating peptide: A means of breaking through the physiological barriers of different tissues and organs. J. Control. Release 309: 106-124.

[38]  Zhang L., Li G., Gao M., Liu X., Ji B., Hua R., Zhou Y., Yang Y., (2016), RGD-peptide conjugated inulin-ibuprofen nanoparticles for targeted delivery of Epirubicin. Colloid. Surf. B. Biointerfaces. 144: 81-89.

[39]  Wang G., Wang Z., Li C., Duan G., Wang K., Li Q., Tao T., (2018), RGD peptide-modified, paclitaxel prodrug-based, dual-drugs loaded, and redox-sensitive lipid-polymer nanoparticles for the enhanced lung cancer therapy. Biomed. Pharmacother. 106: 275-284.

[40]  Guo Y.-N., Lu X., Weng J., Leng Y., (2013), Density functional theory study of the interaction of arginine-glycine-aspartic acid with graphene, defective graphene, and graphene oxide. J. Phys. Chem. C. 117: 5708-5717.

[41]  Muir J. M. R., Costa D., Idriss H., (2014), DFT computational study of the RGD peptide interaction with the rutile TiO2 (110) surface. Surf. Sci. 624: 8-14.

[42]  Uemura Y., Taniike T., Tada M., Morikawa Y., Iwasawa Y., (2007), Switchover of reaction mechanism for the catalytic decomposition of HCOOH on a TiO2 (110) surface. J. Phys. Chem. C. 111: 16379-16386.

[43]  Shariatinia Z., Shahidi S., (2014), A DFT study on the physical adsorption of cyclophosphamide derivatives on the surface of fullerene C60 nanocage. J. Mol. Graph. Model. 52: 71-81.

[44]  Nikfar Z., Shariatinia Z., (2017), Phosphate functionalized (4, 4)-armchair CNTs as novel drug delivery systems for alendronate and etidronate anti-osteoporosis drugs. J. Mol. Graph. Model. 76: 86-105.

[45]  Nikfar Z., Shariatinia Z., (2017), DFT computational study on the phosphate functionalized SWCNTs as efficient drug delivery systems for anti-osteoporosis zolendronate and risedronate drugs. Phys. E: Low-Dimens. Systems Nanostruct. 91: 41-59.

[46]  Shariatinia Z., Nikfar Z., (2013), Synthesis and antibacterial activities of novel nanocomposite films of chitosan/phosphoramide/Fe3O4 NPs. Int. J. Biol. Macromol. 60: 226-234.

[47]  Shariatinia Z., Mazloom-Jalali A., (2020), Molecular dynamics simulations on chitosan/graphene nanocomposites as anticancer drug delivery using systems. Chinese J. Phys. 66: 362-382.

[48]  Shariatinia Z., (2018), Bonding of phosphoramides onto B-C59 nanostructure as drug delivery systems. Phys. Chem. Res. 6: 15-29.

[49]  Vatanparast M., Shariatinia Z., (2019), Hexagonal boron nitride nanosheet as novel drug delivery system for anticancer drugs: Insights from DFT calculations and molecular dynamics simulations. J. Mol. Graph. Model. 89: 50-59.

[50]  Vatanparast M., Shariatinia Z., (2018), Computational studies on the doped graphene quantum dots as potential carriers in drug delivery systems for isoniazid drug. Struct. Chem. 29: 1427-1448.

[51]  Vatanparast M., Shariatinia Z., (2018), AlN and AlP doped graphene quantum dots as novel drug delivery systems for 5-fluorouracil drug: Theoretical studies. J. Fluorine Chem. 211: 81-93.

[52]  Mazloom-Jalali A., Shariatinia Z., (2020), Molecular dynamics simulations on polymeric nanocomposite membranes designed to deliver pipobromane anticancer drug. J. Nanostruct. 10: 279-295.

[53]  Mazloom-Jalali A., Shariatinia Z., (2019), Polycaprolactone nanocomposite systems used to deliver ifosfamide anticancer drug: molecular dynamics simulations. Struct. Chem. 30: 863-876.

[54]  Jalali A. M., Shariatinia Z., Taromi F. A., (2017), Desulfurization efficiency of polydimethylsiloxane/silica nanoparticle nanocomposite membranes: MD simulations. Computat. Mater. Sci. 139:115-124.

[55]  Shariatinia Z., Jalali A. M., Taromi F. A., (2016), Molecular dynamics simulations on desulfurization of n-octane/thiophene mixture using silica filled polydimethylsiloxane nanocomposite membranes. Model. Simul. Mater. Sci. Eng. 24: 035002.

[56]  Gaussian 09, Revision A.02, Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Petersson G. A., Nakatsuji H., Li X., Caricato M., Marenich A., Bloino J., Janesko B. G., Gomperts R., Mennucci B., Hratchian H. P., Ortiz J. V., Izmaylov A. F., Sonnenberg J. L., Williams-Young D., Ding F., Lipparini F., Egidi F., Goings J., Peng B., Petrone A., Henderson T., Ranasinghe D., Zakrzewski V. G., Gao J., Rega N., Zheng G., Liang W., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Vreven T., Throssell K., Montgomery J. A., Jr., Peralta J. E., Ogliaro F., Bearpark M., Heyd J. J., Brothers E., Kudin K. N., Staroverov V. N., Keith T., Kobayashi R., Normand J., Raghavachari K., Rendell A., Burant J. C., Iyengar S. S., Tomasi J., Cossi M., Millam J. M., Klene M., Adamo C., Cammi R., Ochterski J. W., Martin R. L., Morokuma K., Farkas O., Foresman J. B., Fox D. J., (2016), Gaussian, Inc., Wallingford CT.

[57]  Accelrys Software Inc. San Diego, 2009.

[58]  Ghosh P., Bag S., Roy A. S., Subramani E., Chaudhury K., Dasgupta S., (2016), Solubility enhancement of morin and epicatechin through encapsulation in an albumin based nanoparticulate system and their anticancer activity against the MDA-MB-468 breast cancer cell line. RSC Adv. 6: 101415-101429.

[59]  Sun S., Xiao Q.-R., Wang Y., Jiang Y., (2018), Roles of alcohol desolvating agents on the size control of bovine serum albumin nanoparticles in drug delivery system. J. Drug Deliv. Sci. Techn. 47: 193-199.

[60]  Shariatinia Z., Della Védova C. O., Erben M. F., Tavasolinasab V., Gholivand K., (2012), Synthesis, conformational and NQR analysis of phosphoric triamides containing the P(O)[N]3 skeleton. J. Mol. Struct. 1023: 18-24.

[61]  Shariatinia Z., Mousavi H. S. M., Bereciartua P. J., Dusek M., (2013), Structures of a novel phosphoric triamide and its organotin(IV) complex. J. Organom. Chem. 745: 432-438.

[62]  Shariatinia Z., Dusek M., Eigner V., (2014), Synthesis, X‐ray crystallography, and DFT calculations of a novel phosphoramide. Z. Anorg. Allg. Chem. 640: 2945-2955.

[63]  Shariatinia Z., Asadi E., Yousefi M., Sohrabi M., (2012), Novel organotin(IV) complexes of organophosphorus ligands: Synthesis, spectroscopic, structural study and DFT calculations. J. Organom. Chem. 715: 82-92.

[64]  Shariatinia Z., Moghadam E. J., Maghsoudi N., Mousavi H. S. M., Dusek M., Eigner V., (2015), Synthesis, Spectroscopy, X-ray Crystallography, and DFT Computations of Nanosized Phosphazenes. Z. Anorg. Allg. Chem. 641: 967-978.

[65]  Suma N., Aruldhas D., Joe I. H., Anuf A. R., Arun Sasi B. S., (2020), Spectroscopic, quantum chemical, QTAIM analysis, molecular dynamics simulation, docking studies and solvent effect of pyridin-2-yl oxyacetic acid herbicide and its derivatives. J. Mol. Struct. 1206: 127677.

[66]  Mulliken R. S., (1934), A new electroaffinity scale; together with data on valence states and on valence ionization potentials and electron affinities. J. Chem. Phys. 2: 782-793.