Searching for the endogenous benzodiazepine using the graph theoretical approach

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Benzodiazepines are a class of psychoactive drugs known for their anxiolytic, sedative, and anticonvulsant properties.
• Understanding the structural basis of benzodiazepine receptor binding is crucial for developing new therapeutic agents.
• Graph theoretical indices offer a quantitative method to describe molecular topology.

Purpose of the Study:

• To explore structural similarities between known benzodiazepines and potential peptide ligands using graph theory.
• To identify novel peptide sequences that may interact with benzodiazepine receptors.

Main Methods:

• Calculation of graph theoretical indices for various compounds, including diazepam, triazolam, beta-carbolines, purines, and nicotinamide.
• Application of graph theoretical analysis to a library of single amino acids through pentapeptides with modifications.
• Comparison of topological indices between known benzodiazepines and generated peptide sequences.

Main Results:

• Structural similarity was observed between diazepam, triazolam, and the beta-carboline nucleus, correlating with their binding affinities.
• Seven dipeptides and six tripeptides were identified as topologically similar to benzodiazepines and beta-carbolines.
• Key identified dipeptides contain histidine or tryptophan with pyroglutamine, phenylalanine, or tyrosine. Tripeptides feature two aromatic amino acids and pyroglutamine or glycyl termini.

Conclusions:

• The identified dipeptide and tripeptide sequences exhibit topological similarity to benzodiazepines and beta-carbolines.
• These peptides represent promising candidates for interacting with benzodiazepine receptors.
• Their potential biological relevance is supported by their structural characteristics and possible metabolic formation.