Melanin is a widely found natural pigment serving multiple physiological functions and having numerous applications in industries and pharmaceuticals. Due to the diverse structural properties of melanin, drug molecules exhibit varying degrees of affinity towards it. Consequently, drug molecules binding to melanin, including eumelanin, possess significant implications for drug delivery,
... [Show full abstract] biodistribution, and the treatment of various diseases. Here, we investigate allosteric binding between drugs and eumelanin using computational techniques such as molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and free energy calculations. Eumelanin, composed of DHI and DHICA molecules, was utilized in different systems, including aggregated and random arrangements, with the addition of neutral or charged eumelanin and selected drug molecules (chloroquine, levofloxacin, timolol, methotrexate, and diclofenac). The MD simulations revealed conformational changes in both eumelanin and drug molecules upon interaction along with the creation of binding sites or cavities. Evaluation of binding free energy through molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations indicated that neutral timolol and charged diclofenac exhibited the strongest binding to DHI aggregated bundles, while both neutral and charged methotrexate showed the strongest binding in random DHI systems. In contrast, neutral and charged chloroquine displayed the strongest binding in random systems with DHICA (neutral and charged) respectively. Following MD simulations, DFT calculations were employed to further investigate the strength of drug–eumelanin binding. By utilizing the drug–eumelanin poses obtained from MD simulations, DFT calculations demonstrated that the binding strength is influenced by the structural orientation and conformation of both the drug and eumelanin molecules. Overall, drug–eumelanin binding depends on various factors, including conformational changes in both the drug and eumelanin, the charges of the molecules, the presence of binding sites (especially in DHI eumelanin), the occurrence of π–π and hydrogen bond interactions, and the surrounding solvent environment.
