Evaluation Of The Anti-Leishmanial Potential Of Some Prominent Lead Compounds Against Pyridoxal Kinase In Complex With Adenosine Diphosphate And Pyridoxine: A Comparative Study

More than twelve million individuals globally suffer from leishmaniasis, and an additional billion people are at risk in leishmaniasis prevalent areas. This work was motivated by the need to create drugs with high efficacies against leishmaniasis and to overcome the shortcomings of current anti-leishmanial treatments. In this study, a molecular docking investigation was performed to assess the Pyridoxal kinase (PDB ID – 6K91) protein targeting ability of five lead molecules, one each of maleimide, arylimidamide-azole hybrid, arylbenzimidazole, diarylidene cyclohexanone, and organoselenium. The various compounds were further subjected to molecular dynamics (MD) simulation, generalized Born and surface area continuum solvation (MM/GBSA) calculation, drug-likeness assessment, and evaluation of ADMET properties. The overall average binding affinity of the molecules to 6K91 follows the order: B (-10.7 kcal/mol) > C (-10.5) > D (-9.1) > E (-8.7) > SD (-8.1) > A (-7.8 kcal/mol). The MD simulation results indicate these compounds’ favourability and stability in binding to the target in the order; B > SD > C > E > D > A, while their estimated binding free energies in kcal/mol are in the order: B_6K91 (-88.2216) > D_6K91 (-57.4219) > SD_6K91 (-56.7839) > E_6K91 (-51.2518) > C_6K91 (-25.9665) > A_6K91 (unfavorable). The various compounds passed Lipinski’s test and were said to be orally bioavailable, having also good ADMET properties that compare quite well to Pentamidine (standard drug). Conclusively, B (arylimidamide-azole hybrid) demonstrated the best anti-leishmanial attributes, and therefore, could be developed as a potential drug candidate for leishmaniasis.