A Computational Investigation on Eumelanin-Drug Binding in Aqueous Solution
Bibliographic record
Abstract
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, biodistribution, and the treatment of various diseases. Here, we investigate allosteric binding between drugs and eume- lanin 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 eume- lanin 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 di- clofenac 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".