In-Silico Evaluation of Silk Fibroin-Conjugated Doxycycline for Sustained Drug Delivery

Abstract Tetracyclines such as Doxycycline and Minocycline are broad-spectrum antibiotics. Their high oral bioavailability aids systemic absorption but limits achieving sustained local drug levels at the infection site. Sustained drug release to enhance the therapeutic efficacy and minimise side effects remains a significant challenge. This study investigated the conjugation of Doxycycline with silk fibroin (SF), which would provide sustained drug release at the target site. We employed an in-silico approach using molecular docking and molecular dynamics (MD) simulations to investigate the interaction and stability of antibiotics with SF. We also assessed the structural stability of SF when conjugated with these antibiotics. Molecular level characterization using a blind docking approach and MD simulation revealed that Doxycycline exhibited the strongest binding affinity of -6.0 kcal/mol, compared with both Tetracycline (−5.9 kcal/mol) and Minocycline (−5.7 kcal/mol). The MMPBSA analysis also showed that Doxycycline exhibited the highest binding energy of -25.71 kcal/mol compared to Tetracycline (−18.27 kcal/mol) and Minocycline (−10.8 kcal/mol). The strong binding energy and stability of Doxycycline with SF was attributed mainly by van der Waals interactions and hydrogen bonds. To evaluate the stability of protein-antibiotic complexes, 100 ns MD simulations were performed. The RMSD, RMSF, radius of gyration, SASA, and DSSP analyses revealed that SF was stable without much deformation upon docking of all three antibiotics. In summary, our computational results suggest that Doxycycline and SF conjugates offer a promising strategy for sustained drug delivery, potentially improving therapeutic efficacy in the treatment of chronic inflammatory diseases. Highlights - The study finds silk fibroin as a potential carrier for sustained drug delivery of tetracycline family antibiotics. - Silk fibroin remained stable with minimal structural deviations in complex with Doxycycline, Minocycline, and Tetracycline over a 100 ns MD simulation. - Doxycycline showed the highest binding affinity and most favourable binding energy and remained stable throughout the simulation. - SF-Doxycycline conjugate shows promise for sustained, localized drug delivery.