In Silico Assessment of Diketopiperazines as Potential Therapeutic Scaffolds for NTSR1

Diketopiperazines (DKPs) are small, conformationally constrained cyclic dipeptides that have emerged as versatile scaffolds in drug discovery. Their rigid structures, chemical stability, and ability to mimic peptide backbones allow them to engage protein targets with high specificity, making them attractive candidates for receptor modulation. In particular, DKPs can overcome limitations of linear peptides, such as enzymatic instability and conformational flexibility, thereby offering improved pharmacological potential [1].

In this study, we investigated five Type 3 DKPs as potential modulators of Neurotensin Receptor 1 (NTSR1), a Class A G-protein coupled receptor (GPCR) implicated in neurological processes, pain regulation, and cancer progression [2]. The crystal structure of NTSR1 (PDB ID: 4GRV) was used as the receptor model, and molecular docking was performed with AutoDock 4.2 to assess peptide–receptor interactions [3]. All five DKPs demonstrated favorable binding energies, ranging from −4.31 to −7.83 kcal/mol, and engaged key residues within the orthosteric binding pocket. Notably, the compound HIJBAD exhibited the strongest predicted affinity (−7.83 kcal/mol), supported by a network of hydrogen bonding and hydrophobic interactions that suggest enhanced receptor stabilization.

These findings provide evidence that DKPs can serve as stable peptide-mimetic ligands capable of targeting GPCRs such as NTSR1. This work highlights their potential as chemical probes or lead scaffolds for the development of therapeutic agents in neurodegeneration and cancer. Further computational and experimental validation will be essential to fully establish their pharmacological relevance.

1. Bojarska et al., Biomolecules, 2021, 11(10), 1515. https://doi.org/10.3390/biom11101515

2. Huang et al., Nature, 2020, 579, 303–308. https://doi.org/10.1038/s41586-020-1953-1

3. Morris et al., J. Comput. Chem., 2009, 30, 2785–2791. https://doi.org/10.1002/jcc.21256