In Silico Evaluation of Lipid-Drug Conjugates: Pharmacokinetic and Pharmacodynamic Profiling for Therapeutic Repurposing of Naloxone in Migraine Management

Migraine, a common neurological condition, requires novel therapeutic approaches beyond current symptomatic remedies. Drug repurposing offers a rapid-track solution to this demand. Naloxone, an opioid antagonist, has been identified as a potential candidate for migraine treatment, but its limited blood-brain barrier permeability and extensive metabolism limit its clinical effectiveness. Lipid-drug conjugates enhance therapeutic efficiency by chemically conjugating drugs to lipid groups, enhancing lipophilicity and systemic bioavailability, as well as enabling targeted delivery. They facilitate lymphatic targeting (when administered orally) by avoiding first-pass metabolism and prolong the duration of therapeutic action of drug by optimising pharmacokinetic profiles. The present investigation employed In silico methods to study naloxone and its novel naloxone lipid conjugates for altered pharmacokinetic parameters and enhanced interaction with serotonin, toll-like and µ-opioid receptor for the treatment of migraine. Computational ADMET, therapeutic target predictions and molecular docking methodologies were combined for in silico predictions of naloxone and its lipid conjugates. The results revealed that lipid conjugation significantly changed naloxone's pharmacokinetic profiles and binding affinity for serotonin, toll-like and µ-opioid receptor . In silico predictions indicated the potential of naloxone and its lipid conjugates for the treatment of migraine, with results demonstrating that the lipid conjugates provide longer duration of therapeutic action compared to naloxone. This rationale-driven drug repurposing approach has potential for the design of a new, brain-delivered, and serotonin-modulating compound for migraine treatment following in vitro and in vivo validation.