Structure evaluation coupled with all-atom molecular dynamics and advanced quantum mechanical DFT revealed kaempferol...

Aberrant histone deacetylase-9 (HDAC9) activity has been recorded in a plethora of malignant tumors, including gastric cancer, hepatocellular carcinoma, and non-small cell lung cancer. Despite the discovery of HDAC9 as an important pharmacological target, the non-availability of its three-dimensional structure has substantially obstructed the process of discovering potent plant-based therapeutics against it. The present study determined the tertiary structure of human HDAC9 and validated its accuracy. Following this, the binding characteristics of diverse flavonoids against HDAC9 were compared using givinostat as a reference molecule. Moreover, the dynamics of the highest affinity flavonoid and HDAC9 were also investigated in the bound state. Furthermore, the energy gap of the defined flavonoid, signifying the reactivity and kinetic stability, was quantified. We employed multiple techniques, including template-steered modeling, molecular docking, all-atom molecular dynamics, and an atomistic quantum mechanical density functional theory in tandem, for comparing the binding strength of 12 flavonoid molecules against HDAC9 using givinostat (an orphan-approved HDAC inhibitor) as the positive control. Following these procedures, it became discernible that all the flavonoid molecules exhibit stronger binding character and interaction status with this epigenetic target than givinostat. Kaempferol, a flavonol, manifested the strongest affinity among the selected flavonoids and interacted with multiple residues of the deacetylase domain of HDAC9. Similar to givinostat, kaempferol exhibited tenable stability in bound form with this acetylation-eraser enzymatic protein. Most importantly, this flavonol demonstrated higher chemical reactivity and, as such, lower kinetic stability than givinostat which is quite important from a pharmacological perspective.