The guanidine group is one of the strongest organic bases, with a pK<sub>a</sub> of 13.6. The guanidine functionality is also a key component of the essential amino acid L-arginine (L-Arg; R), which is the most basic amino acid, due to its guanidine side chain. Owing to the guanidine high basicity, it is protonated over a wide range of pH conditions, including relevant physiological pHs. The guanidine group forms various intermolecular interactions, especially hydrogen bonds and salt bridges, which play key roles in molecular recognition. As such, the guanidine moiety served over the years as an important functionality for drug development and drug improvement, thereby allowing enhanced binding, selectivity and specificity. Based on these special properties of the guanidine moiety, the current research was conducted in order to identify and clarify its specific role in drugs and drug discovery. For this purpose, we first used data obtained from the FDA and EMA regulatory authorities, as well as other worldwide databases, to retrieve and characterize all the reported and approved guanidine containing drugs. In addition, the Protein Data Bank (PDB) was used to retrieve and analyze the relevant complexes that the guanidine drugs make with their target proteins. A total of 194 such novel guanidine drugs were identified, approved in 1938-2021, about 8.6% of the total drugs approved during this period. These drugs were further analyzed according to their therapeutic categories, their structural diversity, their main biological targets, and possible bio-isosteres of their guanidine groups. In the PDB, a total of 346 drug-target complexes were found for the relevant guanidine-containing drugs, allowing us to identify common hydrogen-bonding patterns and preferred interactions with specific residues of the target proteins. The study demonstrated the central role of the guanidine group in drug-target interactions, as reflected in both binding, orientation and flexibility. The results of this study and the data accumulated in it are expected to be used not only as an important source for the guanidine-containing drugs reported in the past, but also as a key reference for the use of the guanidine moiety as an important element in medicinal chemistry and drug discovery efforts in the future.

Guanidine motif in drug discovery

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