Searching for the endogenous benzodiazepine using the graph theoretical approach.

The graph theoretical indices of several compounds with reported benzodiazepine receptor binding affinities were calculated. Our results demonstrate a structural similarity among diazepam, triazolam, and the beta-carboline nucleus and a structural dissimilarity to the purines and nicotinamide. This result correlates with their respective binding affinities. Using the graph theoretical indices as structural descriptors of the benzodiazepines and the significant ligands of the beta-carbolines, a search for peptide sequences as potential ligands was explored. Single amino acids through pentapeptides with all possible amino acid substitutions and chemical modifications were calculated. The peptides generated were subjected to graph theoretical analysis, and their indices were compared to those of the benzodiazepines. Comparisons resulted in seven dipeptides and six tripeptides that are topologically similar to the benzodiazepines and beta-carbolines. The dipeptides are histidine- or tryptophan-containing compounds with pyroglutamine, phenylalanine, and tyrosine residues in the second position. The tripeptides have two aromatic amino acid residues and a pyroglutamine or glycyl terminal residue. These structures are promising candidates because (1) they are structurally (topologically) similar to the benzodiazepines, represented by diazepam and triazolam, and to the beta-carbolines; and (2) they are sequences that may reasonably form a part of a larger peptide or that may be formed metabolically by proteolysis.