DFT and QM/MM Study of interactions of NSAIDs and Beta‐Blockers with DNA

Abstract This study investigated the interactions of widely used NSAIDs and beta‐blocker drugs with DNA using quantum mechanics with the aim of understanding the applicability of QM models to large systems. Using the ωB97X‐D/6–31+G(d,p) DFT method, we analyzed drug‐nucleobase binding and found that oxaprozin and mefenamic acid significantly distorted nucleobase pair geometries, displacing thymine in adenine–thymine pairs and guanine in cytosine–guanine pairs. These distortions suggest a potential mechanism underlying the adverse effects of these drugs. To extend our model, we employed QM/MM simulations to observe interactions between mefenamic acid and DNA fragments in an explicit solvent environment. Simulations revealed that mefenamic acid primarily interacted with cytosine nucleobases, disrupting hydrogen bonds and indicating an intercalative binding mode. Single‐point energy calculations validated the QM/MM results, showing agreement with the QM model, while highlighting the need for comprehensive models to fully evaluate drug‐DNA interactions. Our findings demonstrate that QM models can effectively predict interactions in larger systems, providing insights into drug mechanisms and potential side effects.