Computational Study on Pazopanib and Pemetrexed Anticancer Drug Molecules Interacting with a Small Peptide Link

Abstract

Cancer is a group of diseases that are defined as uncontrolled cell proliferation, impaired function of vital tissues and cell death. Chemotherapy is treatment using anti-cancer drugs to destroy cancer cells or control the growth of these cells. In chemotherapy applications pharmacologically active anticancer drugs reach with low specificity to tumor tissue, and also their toxicity is dose-dependent. Classical drug administration routes are either oral or intravenous. Orally taken pills result in irregular pharmacokinetics due to the passages of different metabolic pathways and their low specificity. This leads to frequent damage to healthy tissues. Nanoparticle containing drug delivery systems may overcome these harmful side effects partially (or sometimes totally). Binding peptide-drug conjugates inside of some appropriate nanoparticles is one of the prominent methods among targeted drug delivery systems. Such a system containing Pazopanib (Pz) and Pemetrexed (Pm) drug complexes attached to magnetite nanoparticles with a short polypeptide chain (Ala-Lys-Ala-Leu-Arg-Cys) were designed in our laboratory. In the present study, we computationally investigate the conjugation mechanisms of Pz and Pm drug molecules to the above-mentioned polypeptide chain. The stable structures on the complex formation pathways and their free energy values were obtained at the B3LYP/6-31G(d) level in the water. The mechanism of Pept-Pz complex formation has two steps whose free energy barriers are found to be 21.37 and 27.72 kcal/mol. On the other hand, the free energy barrier of the Pept-Pm complex having a single-step mechanism was calculated as 28.16 kcal/mol.