combined qsar modeling, molecular docking screening, and pharmacokinetics analyses for the design of novel 2, 6-diarylidene cyclohexanone analogs as potent anti-leishmanial agents

The current research was conducted as part of the anti-leishmanial drug discovery effort towards new drug molecules with attributes that overcome the limitations of existing therapies. this work utilizes a combined approach of quantitative structure-activity relationship (qsar), virtual docking screening, and pharmacokinetics analysis to design some novel 2,6-diarylidene cyclohexanone analogs using ligand-based drug design methods, while also performing docking investigation, drug-likeness analysis, and molecular dynamic (md) simulation to evaluate their anti-leishmanial potential. some crucial parameters were calculated for the built qsar model, including r2 = 0.7827, r2adj = 0.7206, q2cv = 0.6414, and r2test = 0.8539, which indicate an acceptable qsar model. the combined results of qsar, docking, and pharmacokinetics analysis suggested compound 1 as the template. the six (6) newly designed analogs possessed higher binding scores than the reference drug pentamidine in the order; 1a (-10.2 kcal/mol) > 1e (-9.6) > 1d (-9.4) > 1c (-9.2) > template (-9.1) > 1f (-9) > 1b (-8.5) > pentamidine (-6.9 kcal/mol), while their predicted pic50 followed the order; 1e (8.7321) > 1c (7.6772) > 1f (7.1602) > 1a (6.8289) > 1d (6.7738) > 1b (6.5772) > template (5.3824). the results of the drug-likeness testing suggest 1 and the new analogs (especially 1a) as being orally bioavailable with excellent pharmacokinetic profiles. these molecules equally showed good pharmacological interactions with the receptor, pyridoxal kinase (pdb: 6k91).  in addition, the md simulation results confirmed the stability and rigidity of 1_6k91 and 1a_6k91. therefore, the new analogs could be considered as potent anti-leishmanial inhibitors.