Developing Hispolon based novel anticancer therapeutics against human (NF-κβ) using in silico approach of modelling, docking and protein dynamics.

Hispolon is a polyphenolic compound derived from black hoof mushroom (Phellinus linteus) or shaggy bracket mushroom (Inonotus hispidus) which induces the inhibition of cancer promoting NF-κβ complex. To develop more potent lead molecules with enhanced anticancer efficiency, mechanism of hispolon mediated Nuclear Factor-κβ inhibition has been investigated by molecular modelling and docking. Ten derivatives of hispolon (DRG1-10) have been developed by pharmacophore based design with a view to enhance the anticancer efficacy. Hispolon and its derivatives were further screened for different pharmacological parameters like binding free energy, drug likeliness, ADME, permeability, mutagenicity, toxicity and IC50 to find potent lead molecule. Based on pharmacological validation, comparative MD simulations have been performed for three lead molecules: hispolon, DRG2 and DRG7 complexed with human NF-κβ upto 50ns. By analysing different factors like: RMSD, RMSF, Rg, SASA, PCA, Gibb's free energy plots DRG2 have more binding efficiency compared to hispolon and DRG7. In RMSD plot hispolon bound NF-κβ has the most deviation within a range between 0.125 to 0.45nm and DRG2 bound complex showed the range between 0.125 to 0.25nm. The residues of NF-κβ responsible for hydrophobic interactions with ligand e.g. Met469, Leu522 and Cys533 have lowest fluctuation values in DRG2 bound complex. Average Rg fluctuation for DRG2 bound NF-κβ has been recorded under 2.025nm for most of the simulation time which is much less compared to hispolon and DRG7. Gibb's free energy plots also define the highest stability of DRG2 bound NF-κβ.