Role of Hydroxyl Groups in the B-Ring of Flavonoids on the Mode of DNA Recognition Probed by Myricetin: A Landscape from Nonclassical Hydrophobicity-Driven Groove Recognition to Tuning of Sequestration of a DNA-Bound Drug

Abstract

Exposition of the structure–function relationship through understanding the physicochemical aspects of the interaction of pharmaceutically active small molecules with deoxyribonucleic acid (DNA) is of crucial importance in medicinal research to design new-generation therapeutic agents. Following this, we investigated the interaction of the antioxidant and antitumor polyhydroxyflavone Myricetin (herein after MTN) with naturally occurring calf thymus (CT) DNA, exploring diverse biophysical methodologies. MTN has moderate affinity toward the double-stranded CT DNA with a binding constant of the order of ∼ 103 M–1. Experimental results established that MTN binds to DNA through a groove binding mode. Theoretical blind docking simulation also supported this result. The association was accompanied by a favorable enthalpy change but an unfavorable entropy change. The contribution from each force to the overall binding was quantitatively assessed, which showed that it was the hydrophobic force of a nonclassical nature that governed Myricetin-DNA binding. On the basis of our experimental findings in corroboration with the literature data, we tried to unmask the mystery behind the different preferred binding modes of homologous hydroxyflavones with varying numbers of hydroxyl groups in their B-ring and thereby established the role of hydroxyl groups in that context, which has been a matter of interest over the years. Density functional theory-based calculations were carried out to authenticate the photophysics of MTN. Furthermore, a technique had been developed to excrete the bound drug by exploring surfactant molecules. Further, we tuned the efficacy of the surfactant-induced sequestration phenomenon using stimulants. Overall, we believe that our present study will pave the way for the molecular biology and pharmaceutical industry to cover a wide landscape: from drug designing to drug excretion.