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.