A ۲-D QSAR Modeling, Molecular Docking Study and Design of ۲-Arylbenzimidazole Derivatives as Novel Leishmania Inhibitors: A Molecular Dynamics Study

Leishmaniasis, a neglected tropical disease, affects a human population of over ۱۲ million people, mainly in the tropics, and is caused by the leishmanial parasites transmitted by the female sand fly. The lack of vaccines to prevent leishmaniasis, and the limitations of existing therapies necessitated this study, which was focused on the computational design of some novel ۲-arylbenzimidazole analogs while subjecting the same to molecular docking, pharmacokinetics, and Molecular Dynamic (MD) simulation to ascertain their drug-ability. The obtained QSAR model was validated as follows: R۲ = ۰.۸۴۴۷, R۲adj = ۰.۸۰۹۵, Q۲cv = ۰.۶۷۹۹, and R۲test = ۰.۷۳۸۳. The predicted pIC۵۰ values of all newly designed compounds were higher than that of the lead compound (۱۳). The newly designed analogs conformed to Lipinski's rule for oral bio-availability less ۱۳m, and showed good ADMET properties, with ۱۳j showing the highest Human Intestinal Absorption (HIA) of ۹۳.۶۴%. The MD simulation result demonstrated excellent stability associated with the binding of ۱۳j onto ۶K۹۱'s binding pocket with an estimated ∆G binding (MM/GBSA) of -۵۰.۴۰۳۱ kcal/mol than that of ۱۳_۶K۹۱ (∆G binding = -۲۵.۹۶۶۵ kcal/mol). Therefore, ۱۳j could be recommended as a potential drug molecule for treating leishmanial infections. 

کلیدواژه ها:

Leishmaniasis ، ۲-arylbenzimidazole ، Molecular docking ، ۲-D QSAR ، pharmacokinetics ، Molecular Dynamics