Anticancer compound plumbagin and its molecular targets: a structural insight into the inhibitory mechanisms using computational approaches.

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

Plumbagin (PL) binding to the cavity of Stat3.

<p>Panels A–C: show the (un)binding simulation phases of PL, 'A' is farthest from the binding site, 'B' is the closest to the binding site, and 'C' is the binding site phase. The hydrogen bonds are shown as green-dashed lines with indicated bond length and the residues involved in hydrophobic interactions are shown as red arcs. Those residues which are common to the last phase (C) are encircled. Panel D: Another representation for phase C. The whole protein is displayed in cartoon representation and PL in sticks colored as green. The interacting residues are labeled and shown as surface in different colors.</p

Plumbagin (PL) binding to the cavity of Bcl-2.

<p>Panels A–D: show the (un)binding simulation phases of PL, 'A' is farthest from the binding site, 'C' is the closest to the binding site, and 'D' is the binding site phase. The residues involved in hydrophobic interactions are shown as red arcs. Those residues which are common to the last phase (D) are encircled. Panel E: Another representation for phase D. The whole protein is displayed in cartoon representation and the ligand molecules are in sticks; PL colored as green and the bound known inhibitor in blue. The interacting residues are labeled and shown as surface in different colors.</p