Predicting the effectiveness of combination treatment of dolutegravir and fluoxetine for depressive disorders in HIV

Neurocognitive impairment in people with human immunodeficiency virus (HIV) on antiretroviral therapy is common and may result from persistent HIV replication in the central nervous system (CNS). Depression is a common comorbidity in people with HIV infections, often requiring antidepressant therapy with selective serotonin reuptake inhibitors (SSRIs). SSRIs are the most commonly prescribed antidepressants and can ease symptoms of moderate to severe depression, are relatively safe, and cause fewer side effects. Dolutegravir (DTG)-based regimens are currently the first-line treatment for HIV infection and, when administered with SSRIs, may produce adverse drug reactions. Although the clinical use of DTG is increasing worldwide, limited data are available on its transmission across the BBB, its concentrations in the brain, and its interaction with SSRIs that may contribute to neuropsychiatric effects. To examine the potential drug–drug interaction between DTG and SSRIs, we used CANDOCK (chemical atomic network–based hierarchical flexible docking), a novel docking algorithm that utilizes a hierarchical approach to reconstruct ligands from an atomic grid using graph theory and generalized statistical potential functions to sample biologically relevant ligand conformations that allow predicting drug–ligand binding affinity. We previously showed that DTG and the SSRI sertraline can modulate the expression levels of tight junction proteins and drug transporters proteins, thereby affecting BBB permeability and thus modulating drug penetration, diffusion, and bioavailability of these drugs in the CNS. SSRIs continue to cause less side effects than tricyclic antidepressants; (TCAs), however, no single SSRI has emerged as clearly more effective than others. Our goal was to use CANDOCK to predict the optimal drug–ligand binding affinity for the most commonly prescribed SSRI's fluoxetine, sertraline, and paroxetine in treating depressive disorders in HIV patients. Our study provides a unique perspective on the drug–drug interactions between SSRIs and DTG on the integrity of the BBB and potential implications for progression to HIV-associated neurological disorders (HANDs).