Recent studies have revealed that
MERTK and BRAF V600E receptors have been found to be over-expressed in several types of
cancers including
melanoma, making these receptors targets for drug design. In this study, we have designed novel
peptide conjugates with the natural products
vanillic acid, thiazole-2-carboxylic
acid,
cinnamic acid,
theanine, and
protocatechuic acid. Each of these compounds was conjugated with the
tumor targeting
peptide sequence TAASGVRSMH, known to bind to NG2 and target
tumor neovasculature. We examined their binding affinities and stability with
MERTK and BRAF V600E receptors using molecular docking and molecular dynamics studies. Compared to the neat compounds, the
peptide conjugates displayed higher binding affinity toward both receptors. In the case of
MERTK, the most stable complexes were formed with di-theaninate-
peptide, vanillate-
peptide, and thiazole-2-amido
peptide conjugates and binding occurred in the hinge region. Additionally, it was discovered that the
peptide alone also had high binding ability and stability with the
MERTK receptor. In the case of BRAF V600E, the
peptide conjugates of protocatechuate, vanillate and thiazole-2-amido
peptide conjugates showed the formation of the most stable complexes and binding occurred in the
ATP binding cleft. Further analysis revealed that the number of hydrogen bonds and hydrophobic interactions played a critical role in enhanced stability of the complexes. Docking studies also revealed that binding affinities for NG2 were similar to
MERTK and higher for BRAF V600E. MMGBSA studies of the trajectories revealed that the protocatechuate-
peptide conjugate showed the highest binding energy with BRAF V600E while the
peptide-TAASGVRSMH showed the highest binding energy with
MERTK. ADME studies revealed that each of the compounds showed medium to high permeability toward MDCK cells and were not hERG blockers. Furthermore, the conjugates were not CYP inhibitors or substrates, but they were found to be Pgp substrates. Our results indicated that the protocatechuate-TAASGVRSMH, thiazole-2-amido-TAASGVRSMH, and vanillate-TAASGVRSMH conjugates may be furthered developed for in vitro and in vivo studies as novel
tumor targeting compounds for
tumor cells over-expressing BRAF V600E, while di-theaninate-amido-TAASGVRSMH and thiazole-2-amido-TAASGVRSMH conjugates may be developed for targeting
MERTK receptors. These studies provide insight into the molecular interactions of natural product-
peptide conjugates and their potential for binding to and targeting
MERTK and BRAF V600E receptors in developing new
therapeutics for targeting
cancer.