Identification of Human Epidermal Growth Factor Receptor 2 Antagonist In Silico for Breast Cancer Therapy, Derived from Indonesian Phytochemicals

Abstract

Breast cancer is one of human cancer types that causes high morbidity and mortality rates in the world including Indonesia. Human Epidermal Growth Factor Receptor (HER2) overexpression is found in 25% patients with breast cancer that are assosiated with a poor clinical outcome. Trastuzumab is one of monoclonal antibody (mAb) that be first-line therapy for HER2 overexpressed breast cancer, but administration of this mAb has some side effects and can cause cancer resistancy. Therefore, this study aimed to identification of HER2 antagonist from Indonesian phytochemicals in silico for breast cancer therapy. This biocomputational study used 3D structure of 517 Indonesian phytochemicals which were registered in HerbalDB, Pubchem Databases respectively and fulfill criteria of Lipinski’s rule of five. The 3D structure of trastuzumab-HER2 binding complexes was obtained from Protein Data Bank (PDB), with access code: IN8Z. Trastuzumab and HER2 had large molecule weight, these molecules were truncated. Validation of truncated trastuzumab or phytochemicals and truncated HER2 was determined using the AutoDock Tools version 1.1.2. Visualization of docking results was done using PyMOL version 1.3. Interaction of truncated standard 1 and 2 with truncated HER2 had mean binding energy -4.067 and -4.7 kcal / mol respectively. Arg50 at standard 1 bound to Glu558 and Asp560 HER2, while Gly103 at standar 2 bound to Lys593 HER2. The binding site same as standard 1 was observed in Pulmatin and Gluco-obtusifolin, while (-)-Annonaine and Cinchonain Id had samiliar binding sites with standard 2. All those phytochemicals had lower mean binding energy compared to standard 1 and 2. In conclusion, there were no phytochemicals that interacted with all of HER2 binding sites.