###### Abstract  
In this work, in silico studies were carried out for the design of diterpene and polyphenolpeptide conjugates to potentially target over-expressed breast tumor cell receptors. Four point mutations were induced into the known tumor-targeting peptide sequence YTHWYGYTPQN at positions 1, 2, 8 and 10, resulting in four mutated peptides. Each peptide was separately conjugated with either chlorogenate, carnosate, gallate, or rosmarinate given their known anti-tumor activities, creating dual targeting compounds. Molecular docking studies were conducted with the epidermal growth factor receptor (EGFR), to which the original peptide sequence is known to bind, as well as the estrogen receptor (ER\(\alpha\)) and peroxisome proliferatorator-activated receptor (PPAR\(\alpha\)) using both Autodock Vina and FireDock. Based on docking results, peptide conjugates and peptides were selected and subjected to molecular dynamics simulations. MMGBSA calculations were used to further probe the binding energies. ADME studies revealed that the compounds were not CYP substrates, though most were Pgp substrates. Additionally, most of the peptides and conjugates showed MDCK permeability. Our results indicated that several of the peptide conjugates enhanced binding interactions with the receptors and resulted in stable receptor-ligand complexes; Furthermore, they may successfully target ER\(\alpha\) and PPAR\(\alpha\) in addition to EGFR and may be further explored for synthesis and biological studies for therapeutic applications. p 202212515 20222125 2022125 2022125 2022125 2022125 2022125 202221 2022125 202221 202221 20221 202221 202221 20221 202221 202221 202221 202221 202221 202221 202221 202  
In numerous studies, targeted peptides have been conjugated with drugs to enhance toxicity toward cancer cells and to alleviate adverse side effects caused by lack of specificity in chemotherapeutic drugs [8; 9]. For example, the peptide-drug conjugate \({}^{177}\)Lu-dotatate, composed of somatostatin conjugated with the cytotoxic radiotherapeutic agent \({}^{177}\)Lu, was used to treat gastroenterepancreatic neuroendocrine tumors [10]. Recently, the peptide angiopep-2 was conjugated with the drug paclitaxel, resulting in an increased blood-brain barrier permeation without increasing toxicity [11]. In another study, pH low insertion peptide (pHLIP), a 36-amino acid peptide derived from bacteriorhodopsin, was conjugated with doxorubicin; it demonstrated cancer cell-specific cytotoxicity in MCF-7 breast tumor cells [12]. In a separate study, chlorambucil and camptothecin-peptide conjugates were found to bind to integrin in conformations similar to the bio-active conformation of the parent peptide, as exhibited by molecular dynamics simulations, indicating their potential for use as targeting agents [13]. Naturally occurring plant polyphenols and diterpene derivatives are known for their antioxidant and anticancer properties. These phytochemicals are nontoxic, many are found in the human diet and are therefore promising tools in cancer research [14; 15]. Various mechanisms have been suggested for the anticancer activity of polyphenols [16]. For example, carnostic acid and rosmarinic acid, both derived from the rosmarinus _officinalis_ L.), have been found to exhibit antioxidant properties and anti-carcinogenesis in both tumor initiation and promotion phases [17]. Chlorogenic acid is a component of coffee and many other plants and has been found to possess antioxidant, antibacterial, and anticarcinogenic properties [18]. Gallic acid and curcumin, derived from plant or root sources, have shown antiproliferative properties and can induce apoptosis in cancer cells through regulation of Bax, Bcl-2, and X-linked inhibitor of apoptosis protein (Xiap) [19; 20]. Using computational methods, it was recently reported that the polyphenol quercetin binds to RSK2, a ribosomal kinase which is involved in prostate cancer proliferation [21].