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Abstract
Here, we harnessed the ligand binding interface between the 16-residue peptide (P) agonist to death receptor 5 (DR5), which is unexplored while pivotal for novel and selective cancer drug development, was unexplored. This solitary peptide ligand mimics the TRAIL (the natural ligand to death receptor) and controls cancer growth in vivo selectively, as reported earlier. We delved into the strategic merging of experimental and in silico structure-activity studies via alanine scanning mutagenesis of P, wherein cysteine residues were intact for structural integrity. Synthetic mutants enabled the mapping of the interaction engagement of each residue via antiproliferative activity studies on HCT116 cells. Further, in silico docking and MD simulations led us to interpret and model the 3D-binding interface between the P and DR5 protein. Notably, Trp1, Leu4, Arg7, Ile8, Gln12, and Arg15 were projected as ‘hot-spot’ residues crucial for primary interactions with DR5, which predominantly supports in silico investigations.
Supplementary materials
Title
We harnessed the ligand binding interface between the 16-residue peptide (P) agonist to death receptor 5 (DR5), which is unexplored while pivotal for novel and selective cancer drug development, was unexplored.
Description
In a structure-based drug discovery program, understanding a ligand binding interface to target molecules and interaction modules are crucial steps for furthering the development of new hits and novel drugs. We were drawn to reveal the potential interaction model of the DR5-P complex for future peptide drug discovery in treating cancer selectively. Trp1, Leu4, Arg7, Ile8, Gln12, and Arg15 were projected as ‘hot-spot’ residues crucial for primary interactions with DR5, which predominantly supports in silico investigations. This fundamental study will allow the development of novel and better peptide ligand agonists to DR5 for specific cancer treatment.
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