The main aim of this study is to screen and develop Peptidomimetics to treat atherosclerosis (AS) which is a Cardio Vascular Disease (CVD). Peptidomimetics were obtained from the protein-protein interaction interface of TRADD (Tumor necrosis factor receptor type 1-associated DEATH domain protein) and TRAF2 (TNF receptor-associated factor 2) complex. TRADD-TRAF2 interaction is critical in AS pathogenesis since it assists a series of signal transducers that activate NF-κB. Conceptually, 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) and its interaction details revealed that the sequence range W11-G165 of TRADD highly interacts with TRAF2. The sequence range W11-G165 was selected for the design and preparation of the inhibitory peptide in silico. The selected sequence was mutated with the alanine scanning method to have a range of inhibitory peptides. With the help of different in silico tools, the top three, namely MIP11-25 L, MIP131-143 h, and MIP149-164 m peptides showed the best interaction with the critical residues of TRAF2. Thus, these three peptides were used for generating peptidomimetics using pepMMsMIMIC, a peptidomimetics virtual screening tool. Around 600 peptidomimetics were identified & and retrieved for further screening by employing molecular docking tools and MD (Molecular Dynamics) simulations. Density Functional Theory (DFT) and ADMET predictions were applied to validate the screened peptidomimetics druggability. In the results, peptidomimic compounds MMs03918858 and MMs03927281 with binding energy values of -9.6 kcal/mol and - 9.1 kcal/mol respectively were screened as the best and are proposed for further pre-clinical studies.
Keywords: ADMET; Alanine scanning; Atherosclerosis; CVD; Peptidomimetics.
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