Computational Model of Doxorubicin Conjugate with Docosahexaenoic Acid and Integrin avß3 Ligand for Anticancer

Abstract

Doxorubicin (DOX) is one of the most effective drugs for cancer treatment. However, the undesired side effects of DOX towards cardiotoxicity and drug resistance have raised concern about developing the safer medication. Therefore, the potency of DOX can be optimized by conjugating it with the other molecules. Integrin α v β 3 receptor which overexpressed in cancer cells can be used as a target for specific therapeutics. Fatty acids such as docosahexaenoic acid (DHA) is also known to improve the absorption of DOX in the cancer cell. Therefore, for the first time, the possibility of a conjugated drug composed of three components, i.e. DOX, integrin ligand, and DHA, is explored using the computational methods. This study aimed to propose a computational model of DOX conjugate with α v β 3 integrin ligand and DHA using structure-based design approach and to predict the pharmacokinetic properties of each component using in silico method. A peptidomimetic ligand was used as a template to develop new integrin ligand. Molecular docking was used to predict the best binding mode and energy of the ligand to enhance the selectivity of DOX conjugate. Molecular dynamics showed the stable binding of integrin ligand. In silico pharmacokinetics Key words:DHA, integrin α v β 3 , a computational model.

Cellular Basis of Adjuvant Role of n-3 Polyunsaturated Fatty Acids in Cancer Therapy: Molecular Insights and Therapeutic Potential against Human Melanoma

“…Computational methods based on structure-based design were used to explore the potential of a conjugated drug, predicting the pharmacokinetic properties of each component and identifying the best binding mode and energy to enhance the selectivity of the doxorubicin-DHA conjugate. These in silico approaches indicate that DHA might significantly improve the overall permeability and efficacy of doxorubicin in targeting cancer cells [41]. Some of the other drug interactions will be discussed in Section 4.…”

Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review

“…Some scientists used in silico computational modelling for new hybrids to predict their pharmacokinetics (binding affinity, cytotoxicity, modes of action, etc.) on tumor cell lines as well as normal cells [ 57 , 58 , 59 , 60 , 61 , 62 ]. Furthermore, molecular dynamic simulation is one of the powerful computational tools used to predict the information about interactions and physicochemical mechanisms of the drug [ 57 ].…”

“…Furthermore, molecular dynamic simulation is one of the powerful computational tools used to predict the information about interactions and physicochemical mechanisms of the drug [ 57 ]. This method has been used to study doxorubicin loaded in nanomaterials (e.g., nanocarriers and nanoparticles) by different researchers [ 57 , 58 , 59 , 60 , 61 , 62 ]. However, there is no published information on the use of this method for hybrid organic molecules containing doxorubicin scaffolds.…”