Cholinergic drugs bind at the minor groove and reverse induced oxidative stress of calf thymus DNA: a new perspective towards an unexplored therapeutic efficacy

Abstract

Conformational alterations in the structure of deoxyribonucleic acid (DNA) due to oxidative stress in the DNA backbone are known to be at the root of many life-threatening diseases. Clear comprehension...

Auxiliary Therapeutic Role of Cholinergic Agents: Mechanistic Insights into the Antioxidant Behavior of Alzheimer’s Disease Drugs

“…The fluorescence of the DNA-EB system (50 μM) increases on adding H 2 O 2 (30%, 0.5 mM) due to the oxidative damage in the presence of peroxide, resulting in a change in the structure. 19 However, the fluorescence intensity almost returns to the native DNA-EB fluorescence on adding the AD drugs. The ability of the investigated drugs to decrease the DNA-EB fluorescence intensity despite the presence of H 2 O 2 implies the reversal of induced oxidative stress in DNA.…”

“…The three-dimensional (3D) structure of calf-thymus DNA (ct-DNA) in its widely studied D-form is retrieved from the Protein Data Bank, and the docking process is monitored with AutoDock Vina 61 following the same methodology discussed earlier. 19 The bestdocked poses are created using Discovery Studio Visualizer and used for drug−base interaction analysis. The results indicate that all of the studied compounds bind at the minor groove of ct-DNA with considerable binding energy.…”

“…18 However, recent experimental studies confirm that several cholinergic drugs, approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease (AD), reverse the oxidative stress induced by radicals and also bind at the minor groove of calf-thymus DNA, thus causing no damage to its structural features. 19 The antioxidant property of these AD drugs, coalesced with their harmless association with DNA, presents an alternative way of reversing ROS-mediated DNA stress through a radical scavenging process at the binding locale. Since the effectiveness of these compounds in reversing the DNA damage directly correlates to their antioxidant strength, it is thus important to investigate the thermodynamic and kinetic factors governing this property in detail.…”

“…25−27 Experimental studies on the antioxidant property of a few cholinergic drugs have been reported in the literature. 19,28,29 However, a thorough and comparative understanding of the mechanistic details of the antioxidant property for these systems has not been explored yet. A theoretical understanding of the detailed thermodynamics and kinetics of the antioxidant behavior in these drugs is important to identify the key parameters leading to the observed antioxidant property (and preferentially groove binding), such that new and more efficient systems can be designed and developed from these molecular scaffolds, having both acetylcholinesterase (AChE) inhibition and antioxidant behavior.…”

“…It is already established that most of the drugs, particularly of anticancer, cytostatic, and psychotropic groups, are genotoxic in nature due to their intercalation with DNA, which provokes significant conformational changes in its structural features and directly disrupts the genomic sequence. − In fact, while many flavonoid groups of compounds are known for their antioxidant properties, a number of them are reported to be DNA intercalators also . However, recent experimental studies confirm that several cholinergic drugs, approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease (AD), reverse the oxidative stress induced by radicals and also bind at the minor groove of calf-thymus DNA, thus causing no damage to its structural features . The antioxidant property of these AD drugs, coalesced with their harmless association with DNA, presents an alternative way of reversing ROS-mediated DNA stress through a radical scavenging process at the binding locale.…”