title: Anticancer compound plumbagin and its molecular targets: a structural insight into the inhibitory mechanisms using computational approaches.
abstract: Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naphthoquinone derivative from the roots of plant Plumbago zeylanica and belongs to one of the largest and diverse groups of plant metabolites. The anticancer and antiproliferative activities of plumbagin have been observed in animal models as well as in cell cultures. Plumbagin exerts inhibitory effects on multiple cancer-signaling proteins, however, the binding mode and the molecular interactions have not yet been elucidated for most of these protein targets. The present study is the first attempt to provide structural insights into the binding mode of plumbagin to five cancer signaling proteins viz. PI3Kγ, AKT1/PKBα, Bcl-2, NF-κB, and Stat3 using molecular docking and (un)binding simulation analysis. We validated plumbagin docking to these targets with previously known important residues. The study also identified and characterized various novel interacting residues of these targets which mediate the binding of plumbagin. Moreover, the exact modes of inhibition when multiple mode of inhibition existed was also shown. Results indicated that the engaging of these important interacting residues in plumbagin binding leads to inhibition of these cancer-signaling proteins which are key players in the pathogenesis of cancer and thereby ceases the progression of the disease.
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Jamal
authors.affiliation: Bareilly College, M.J.P. Rohilkhand University, Bareilly, U.P., India.
authors.forename: Shadma
authors.initials: S
authors.lastname: Parveen
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohd A
authors.initials: MA
authors.lastname: Beg
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohd
authors.initials: M
authors.lastname: Suhail
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Adeel G A
authors.initials: AG
authors.lastname: Chaudhary
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Ghazi A
authors.initials: GA
authors.lastname: Damanhouri
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Adel M
authors.initials: AM
authors.lastname: Abuzenadah
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohd
authors.initials: M
authors.lastname: Rehan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism; D062313:Databases, Pharmaceutical; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism; D009285:Naphthoquinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008024:Ligands; D016328:NF-kappa B; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D058544:Class Ib Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; C014758:plumbagin