Amino acid decomposition analysis of natural anthraquinones within cancer relevant chemotherapeutic targets

Introduction and Background: A set of natural anthraquinones (AQs) were subjected to the combined in silico structure-based/quantum mechanical studies versus cancer relevant biochemical targets with the aim of proposing favorable anticancer mechanism(s). Selected chemotherapeutic targets were formerly known to be inhibited by AQs. Methods: Genetic algorithm of AutoDock version 4.2 with incorporated MGL tools-1.5.7 was applied to elucidate the most probable binding interactions of selected AQs within active sites of cancer-relevant targets. Subsequently, docked AQ molecules were aubjected to amino acid decomposition analysis via analysis of intermolecular binding energy components by functional B3LYP in association with split valence basis set using polarization functions (Def2-SVP). The whole calculations were performed with the ORCA quantum chemistry package. LIGPLOT program was utilized to monitor the intermolecular interactions. Results: Studied AQs exhibited different binding modes/energies through hydrophobic/hydrophilic binding pockets of macromolecular targets. It was revealed that hydrophobic nature of AQ core structure facilitated interactions with residues of c-Met kinase, PKC, and Akt active sites. Furthermore; appropriate substitution of hydroxyl , carboxyl and acetate functional groups within AQ scaffold might give rise to additional H-bond attraction forces with residues of PIK3 active site and this was the case for Diacerein. Disscusion and Conclusion: Structure binding relationship studies of natural AQs with different substituents demonstrated the binding affinity of each compound that was previously proved to inhibit such targets. To our best knowledg, no studies have been dedicated to the amino acid decomposition analysis of AQs as anticancer agents and results of this study may further extend the scope of natural AQs as privileged structures in cancer chemotherapy