Drugs repurposed against morphine and heroin dependence: molecular docking, DFT, MM-GBSA-based MD simulation studies

Morphine and heroin dependence are growing concerns worldwide. Drug dependence is one of the greatest challenges, and developing alternative therapeutic strategies is essential. Due to few treatment options in pain management, morphine, a potent analgesic, is widely prescribed, but it carries a high risk of abuse. For the management of drug dependence, we have limited treatment options available, therefore, strategies should be developed to manage drug-seeking behaviors in clinical settings. We tried to find any FDA-approved drug targeting µ-opioid receptors through the in-silico approach. We screened around 186 FDA-approved drugs; we observed several drugs showing better docking scores with good affinity. We found vilazodone, indinavir, and lorazepam as potential drugs based on their affinity and mechanism of action. Later, these drugs were screened against human µ-opioid (PDB ID:8EF6) and other novel drug targets (5HT1 and TLR-4) that are associated with morphine dependence. Following docking, density functional theory (DFT), molecular dynamics (MD), molecular mechanics, and general born surface area (MM-GBSA) were performed to calculate the stability and ligand-protein binding free energies. Vilazodone, indinavir and lorazepam showed promising docking, MD, the energy gap between the HOMO and LUMO chemical reactivity, and MM-GBSA results compared to morphine and naloxone. We propose that these three drugs have huge potential to reverse the morphine and heroin dependence in diseased subjects near future.

The online version contains supplementary material available at 10.1007/s40203-025-00347-z.