Melittin as a Potential Inhibitor of HIV‐1 Reverse Transcriptase: An in Silico Approach

ABSTRACT

Melittin, a major amphipathic component of honey bee venom, is well known for its broad antimicrobial activity and has been implicated in the disruption of viral proteins. In this study, we investigated the potential of short melittin‐derived fragments as inhibitors of HIV‐1 reverse transcriptase (RT) through the implementation of an integrated in silico workflow. The 26‐residue melittin was systematically fragmented into 4‐14‐residue peptides, yielding a non‐redundant set of 168 unique melittin‐derived fragments. Docking calculations were performed and eight peptide‐RT complexes were subsequently selected for molecular dynamics (MD) simulations and analysed with respect to RMSD, RMSF, hydrogen‐bonding, protein–peptide minimum distance and SASA, followed by MM/GBSA binding free‐energy calculations. A total of 49 peptides attained docking scores ≤ −8.0 kcal/mol, predominantly engaging NNRTI‐site residues Val90, Gly93, Gln161, Lys101, Tyr181, and Met184. MD and MM/GBSA analyses showed complementary profiles, with Mel‐8‐19 exhibiting the most favourable binding free energy, while Mel‐13‐19, Mel‐12‐21 and Mel‐4‐13 showed favourable structural stability. Post‐MD developability screening identified Mel‐4‐13 and Mel‐10‐19 as relatively balanced candidates, whereas Mel‐8‐19 was predicted to be haemolytic. These computational findings identify melittin‐derived fragments for further investigation. Their ability to inhibit HIV‐1 RT remains to be established experimentally.