Mechanism of drug-potency enhancement <i>via</i> methylation

In the past decade, the effect of methyl groups on drug molecules has gained increasing interest in medicinal chemistry. Recent research has shown that the methyl group enhances the pharmaceutical potency and specificity of drugs, a phenomenon commonly referred to as the "magic methyl effect". A site-selective introduction of methyl group(s) into drug molecules can often modify several of their pharmaceutical properties, including drug potency, biological activity, pharmacodynamics, and pharmacokinetics. The current literature qualitatively suggests that this potency enhancement <i>via</i> targeted methylation is the effect of the alteration of physical parameters, like drug solubility, hydrophobicity, and conformational change. However, a quantitative thermodynamic framework that can be used as a design tool to enhance the drug potency using these parameters is missing. We aim to understand this effect from a thermodynamic standpoint by considering drug molecules and proteins. All-atom molecular dynamics simulations and molecular docking were performed to obtain thermodynamic parameters, including the binding free energy, polarity, and conformational change. We developed a correlation to quantify the polarity of protein cavities based on the hydropathy index. Our analysis showed that the conformational changes resulting from methylation are key factors influencing drug potency in both hydrophilic and hydrophobic protein cavities. Additionally, the methyl effect is position-specific, and we defined how to quantify an optimum position for methylation that leads to higher enhancement. Finally, this study provides guidance for the incorporation of methyl groups into drug molecules to enhance their potency, which has implications in healthcare and pharmaceuticals.