Differential algorithms-assisted molecular modeling-based identification of mechanistic binding of ganoderic acids

Abstract

Ganoderma, in the recent years, has been comprehensively characterized and held invaluable for their miscellaneous pharmacological activities. Recently, attempts to explore and fathom the pathway of inhibition revealed GA-A and GA-H to impede the progression of breast cancer by inhibiting the signaling of AP-1 and NF-κB, although the mechanism has not yet been explored. NF-κB is a key transcription factor having irrefutable role in cell proliferation, apoptosis and cancer signaling and its subunits κB-IKKα, IKKβ and IKKγ (NEMO) are pivotal to the cancer signaling mechanism. The present study confirmed mechanistically the association between NF-κB and NEMO in regulating the signaling cascade of NF-κB. GA-A and GA-H were observed to participate in various non-covalent interactions, thus contributing largely to the stability of the ligand–macromolecules association as well as their role as anticancer agent in breast cancer. Amino acids, Lys90 and Asn732, were seen to be critically involved in the signaling cascade. Apart from this, residues Glu98 and Met94, Cys95 and Glu91 were involved in hydrogen bonding in GA-A and GA-H. The anticancer activity exhibited by GA-A and GA-H is attributed to certain docking poses and interaction that were found to be absent in the GA-F such as hydroxylation at 3 and 7 and/or 15 in the lanostane structure. This study is the first of its kind elucidating a possible mode of binding of ganoderic acid in NF-κB signaling pathway using molecular modeling studies, further evaluated by differential calculation-based algorithms.