Peptidomimetics for CVD screened via TRADD-TRAF2 complex interface assessments

Abstract This study aimed to screen and develop a few Peptidomimetics to treat Cardio Vascular Disease (CVD). Designed peptidomimetics from peptides generated from the protein interacting region of TRADD (Tumor necrosis factor receptor type 1-associated DEATH domain protein) and TRAF2 (TNF receptor-associated factor 2) complex which is critical in Atherosclerosis (AS) pathogenesis as it assists in a series of signal transducers that activates NF-κB. The triggered NF-κB makes an extensive amount of nitric oxide (NO) synthesized by inducible nitric oxide synthase (iNOS), which boons the progress of AS. The examined TRADD-TRAF2 complex (PDB ID: 1F3V) from the previous study indicates that the sequence range W11-G165 of TRADD highly interacts with TRAF2. The sequence was selected for inhibitory peptide design. Further, the selected sequence was mutated with the alanine sequence to have a variety of peptide ranges. And with the help of different silicon tools, the top three, MIP11-25l, MIP131-143h, and MIP149-164m showed the best interaction with critical residue. pepMMsMIMIC is a virtual screening tool mainly based on a multi-conformers three-dimensional (3D)-similarity search strategy. 600 peptidomimetics were identified & retrieved for further screening over molecular docking and MD (Molecular Dynamics) simulations. Density Functional Theory (DFT) and ADMET predictions also applied in order to validate the screened peptidomimetics compounds druggability. In the results, pepmimic compounds MMs03918858 and MMs03927281 with binding energy values of -9.6 kcal/mol and − 9.1 kcal/mol respectively were screened as best and are proposed for further pre-clinical studies.