Multi Targeted Ligands for Potential Inhibition of Dipeptidyl Peptidase 4, Acetylcholinesterase and Cyclooxygenase 2

Abstract

Two series of novel compounds were designed by combining indomethacin and ibuprofen with sixteen sulfa drugs. These compounds were systematically evaluated through target fishing using the Pharm Mapper, leading to the identification of DPP-4, AChE, and COX-2 as potential targets. Molecular docking was performed to evaluate the binding affinity of designed compounds against the identified three target proteins. The results revealed that the designed compounds exhibited binding affinities ranging from ~8 to -12kcal/mol, 12 to 13 kcal/mol and 8 to 11kcal/mol for DPP-4, AChE and COX-2 respectively. The binding affinities were found to be comparable or higher than binding affinity of co-crystallized ligand, which was found to be ~10, 12 and 9 kcal/mol respectively. Further investigation into the binding modes of these compounds was carried out. Notably, for DPP-4 complexes, interactions with Arg125, Glu205, and Glu206 were observed which are essential for substrate and inhibitor binding. For AChE complexes, interactions involved crucial His447 residues, essential for acetylcholine hydrolysis. In the case of COX-2, hydrogen bond interaction was noted with Arg120 located at the entrance of the hydrophobic channel. Despite favorable binding potentials, ADME profiling highlighted five compounds (1A, 1F, 1G, 1H, and 1O) with drug-like characteristics but lacking blood-brain barrier permeation ability. Out of five compounds, 1H stood out, demonstrating superior binding affinity and interactions vital residues necessary for catalytic activity of three enzymes. Thus, 1H emerges as a promising candidate for Multi-Targeted Drug-Like (MTDL) development aimed at addressing diabetes mellitus related dementia.