Hybrid descriptors–conjoint indices: a case study on imidazole-thiourea containing glutaminyl cyclase inhibitors for design of novel anti-Alzheimer’s candidates

Clinical studies show that the pyroglutamate alteration of amyloid-β (Aβ) catalysed by metalloenzyme glutaminyl cyclase results in the formation of the more neurotoxic pGlu-Aβ, and inhibition of glutaminyl cyclase can bring down the load of pGlu-Aβ in the brain and reduces Alzheimer's disease pathology with improvement in cognition. The present study involves the identification of activity-modulating structural features of 188 inhibitors of glutaminyl cyclase under the influence of index of ideality of correlation (IIC) and correlation intensity index (CII) as prediction parameters. The QSAR models developed employing IIC and CII were found to be statistically better and had better predictability than the models developed without them. The best model (split 4) showed r2 values of 0.8155 and 0.8218 for calibration and validation sets, respectively. The structural features classified from QSAR models were used to design some new glutaminyl cyclase inhibitors. Among the designed ligands, ligand 5 possesses the highest pIC50 value (6.30) as well as binding affinity (-6.2 kcal/mol) and creates hydrogen bonds with TRP 329, π-alkyl interactions with ILE 303 and TYR 299, π-π stacking interaction with PHE 325 and interactions with ZN 391. All novel designed ligands have better pIC50 values and binding affinities.