Document Type : Original Research Article
Authors
Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B. 1044, Zaria, Kaduna State, Nigeria
Abstract
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.
Graphical Abstract
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Highlights
- The high limitations of existing therapies resulting in pending cases of leishmanial diseases necessitated the study.
- A computer-aided design of novel 2, 6-diarylidene cyclohexanone analogs as anti-leishmanial agents; 2-D QSAR, molecular docking, pharmacokinetics, and MD simulation were conducted to investigate the anti-leishmanial activities, binding interaction pattern, drug-likeness properties, and the stability of protein-ligand complexes of the newly designed analogs.
- The resulting docking scores were used to identify the best protein-ligand interaction pairs, while the docked poses were post-screened and analyzed for helpful information on binding/pharmacological interactions.
- The generated 2-D QSAR data were subjected to some relevant validation tests in order to qualify the model.
- Also, the newly designed analogs were subjected to pharmacokinetic analysis in order to ascertain their drug-likeness properties, while the protein-ligand complexes of 1 and 1a were analyzed for binding stability using the result of MD simulation.
- The combined results of the study lead to the identification of compound 1a as a potential drug candidate for the treatment of leishmanial infections.
Keywords
- Leishmaniasis
- Diarylidene cyclohexanone
- 2-DQSAR
- Molecular docking
- Pharmacokinetics
- Molecular dynamics
Main Subjects
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