Fabian Ugbe - Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B. ۱۰۴۴, Zaria, Kaduna State, Nigeria
Gideon Shallangwa - Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B. ۱۰۴۴, Zaria, Kaduna State, Nigeria
Adamu Uzairu - Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B. ۱۰۴۴, Zaria, Kaduna State, Nigeria
Ibrahim Abdulkadir - Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B. ۱۰۴۴, Zaria, Kaduna State, Nigeria

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 ۲,۶-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 R۲ = ۰.۷۸۲۷, R۲adj = ۰.۷۲۰۶, Q۲cv = ۰.۶۴۱۴, and R۲test = ۰.۸۵۳۹, which indicate an acceptable QSAR model. The combined results of QSAR, docking, and pharmacokinetics analysis suggested compound ۱ as the template. The Six (۶) newly designed analogs possessed higher binding scores than the reference drug Pentamidine in the order; ۱a (-۱۰.۲ kcal/mol) > ۱e (-۹.۶) > ۱d (-۹.۴) > ۱c (-۹.۲) > Template (-۹.۱) > ۱f (-۹) > ۱b (-۸.۵) > Pentamidine (-۶.۹ kcal/mol), while their predicted pIC۵۰ followed the order; ۱e (۸.۷۳۲۱) > ۱c (۷.۶۷۷۲) > ۱f (۷.۱۶۰۲) > ۱a (۶.۸۲۸۹) > ۱d (۶.۷۷۳۸) > ۱b (۶.۵۷۷۲) > Template (۵.۳۸۲۴). The results of the drug-likeness testing suggest ۱ and the new analogs (especially ۱a) as being orally bioavailable with excellent pharmacokinetic profiles. These molecules equally showed good pharmacological interactions with the receptor, Pyridoxal kinase (PDB: ۶K۹۱).  In addition, the MD simulation results confirmed the stability and rigidity of ۱_۶K۹۱ and ۱a_۶K۹۱. Therefore, the new analogs could be considered as potent anti-leishmanial inhibitors.

Leishmaniasis, Diarylidene cyclohexanone, ۲-DQSAR, Molecular docking, pharmacokinetics, Molecular Dynamics