Molecular interactions profiling of 1,2,3-triazol based ligands and proteins co-crystals: A data mining approach

CARLUCCI, RENZO; LISA, MARÍA-NATALIA; LABADIE, GUILLERMO R.

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofísica

Rational design and development of small molecules is an important and changeling area in drug discovery. Recently, the 1,2,3-triazole (123T) scaffold has become very attractive to identify new chemical entities in drug discovery projects and also in diverse chemical-biology applications.Structural biology have a central role in drug discovery, with a constant growth in the number of entries in public databases that have high impact in the scientific community, i.e. wwPDB (>200000 entries), DrugBank (>500000 entries) and ChemBL (>2300000 entries). These databases are a source of inspiration for medicinal chemists and other scientists who seek for molecular entities to challenge complex biological systems. Among existing practical strategies there is a group that uses structural information as primary source of decision-making, called Structure-Based Drug Discovery approaches. Despite the extensive use of click chemistry to prepare numerous 123Ts (22588 records ChemBL) there are few drugs in the market that bear the 123T scaffold as substructure (5 records DrugBank). To investigate the real value of 123Ts to identify new enzyme inhibitors, we decided to examine the non-covalent interactions between 123T’s ring and amino acids (AA) from protein-ligand co-crystals by inquiring their structures using a geometrical approach. For this, we constructed a non-redundant database of PDB IDs from available 123T-protein co-crystals structures. Then, by using the Protein Ligand Interaction Profiler web platform (PLIP), we sought to determine if 123Ts have served mostly as mere pharmacophore linkers´, or if it could be considered an interactive scaffold. Next, we manually mined the geometrical descriptors from interactions between 1,4-disubstitued 123T rings and AA residues in proteins. Finally, we discussed the more frequent interactions found to understand 123Ts ring’s interaction-potential with proteins. The present study has shown that 123T have different preferred interactions with AAs that contributed to enzyme binding. Those interactions would contribute to the stability of enzyme-inhibitors complexes, being important when new drugs are designed.