TY - JOUR ID - 165482 TI - Combined QSAR Modeling, Molecular Docking Screening, and Pharmacokinetics Analyses for the Design of Novel 2, 6-Diarylidene Cyclohexanone Analogs as Potent Anti-Leishmanial Agents JO - Progress in Chemical and Biochemical Research JA - PCBR LA - en SN - 2676-7090 AU - Ugbe, Fabian Audu AU - Shallangwa, Gideon Adamu AU - Uzairu, Adamu AU - Abdulkadir, Ibrahim AD - Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B. 1044, Zaria, Kaduna State, Nigeria Y1 - 2023 PY - 2023 VL - 6 IS - 1 SP - 11 EP - 30 KW - Leishmaniasis KW - Diarylidene cyclohexanone KW - 2-DQSAR KW - Molecular docking KW - pharmacokinetics KW - Molecular Dynamics DO - 10.22034/pcbr.2022.366493.1234 N2 - 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. UR - https://www.pcbiochemres.com/article_165482.html L1 - https://www.pcbiochemres.com/article_165482_c67e147fe9f3ac25c19a68fe0ee415bf.pdf ER -