Peptidomimetics for CVD screened via TRADD-TRAF2 complex interface assessments

Area of Science:

• Biochemistry and Molecular Biology
• Cardiovascular Disease Research
• Drug Discovery and Development

Background:

• Atherosclerosis (AS) is a significant cardiovascular disease (CVD) exacerbated by the TRADD-TRAF2 protein interaction.
• This interaction activates NF-κB, leading to nitric oxide (NO) production via inducible nitric oxide synthase (iNOS), promoting AS.
• Targeting the TRADD-TRAF2 interface presents a potential therapeutic strategy for AS.

Purpose of the Study:

• To screen and develop peptidomimetics as potential therapeutics for atherosclerosis.
• To design inhibitors targeting the critical protein-protein interaction between TRADD and TRAF2.
• To identify druggable peptidomimetic compounds for preclinical evaluation.

Main Methods:

• In silico design of inhibitory peptides based on the TRADD-TRAF2 interaction interface (PDB ID: 1F3V).
• Peptide optimization using alanine scanning and virtual screening with pepMMsMIMIC.
• Molecular docking, Molecular Dynamics (MD) simulations, Density Functional Theory (DFT), and ADMET predictions for compound validation.

Main Results:

• Identified three lead inhibitory peptides (MIP11-25L, MIP131-143h, MIP149-164m) with strong TRAF2 binding.
• Generated and screened approximately 600 peptidomimetics, identifying promising drug candidates.
• Two peptidomimics, MMs03918858 and MMs03927281, exhibited high binding affinities (-9.6 and -9.1 kcal/mol, respectively).

Conclusions:

• Peptidomimetics targeting the TRADD-TRAF2 interaction are viable therapeutic candidates for atherosclerosis.
• MMs03918858 and MMs03927281 demonstrate significant potential based on binding energy and druggability predictions.
• These compounds are recommended for further preclinical studies to assess their efficacy in treating atherosclerosis.