Discovery of Dual Targeting GSK-3β/HIV-1 Reverse Transcriptase Inhibitors as Neuroprotective Antiviral Agents

Abstract

Glycogen synthase kinase-3 beta (GSK-3β or GSK-3B) is a serine–threonine kinase involved in various pathways and cellular processes. Alteration in GSK-3β activity is associated with several neurological diseases including Alzheimer’s disease (AD), bipolar disorder, and rare diseases like Rett syndrome. GSK-3β is also implicated in HIV-associated dementia (HAD), as it is upregulated in HIV-1-infected cells and plays a role in neuronal dysfunction. Therefore, a small molecule that can inhibit both GSK-3β and HIV-1 reverse transcriptase could offer neuroprotective therapy for patients suffering from HIV-1. Despite this, there are no known GSK-3β inhibitors currently approved, thus prompting us to screen our panel of various antiviral compounds against this kinase to better understand its structure–activity relationship. We show for the first time that the approved drugs, etravirine and rilpivirine, possess GSK-3β activity (IC₅₀ 619 nM and 502 nM, respectively). We have also identified 3 lead molecules exhibiting IC₅₀ < 1 μM (11726169, 12326205, and 12326207), with compound 11726169 being the most potent in vitro GSK-3β inhibitor (IC₅₀ = 12.1 nM). We also describe the generation of machine learning models for GSK-3β inhibition and their validation with our data as an external test set and propose their use for the future optimization of such inhibitors.