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

Glycogen synthase\nkinase-3 beta (GSK-3β or GSK-3B) is a serine–threonine\nkinase involved in various pathways and cellular processes. Alteration\nin GSK-3β activity is associated with several neurological diseases\nincluding Alzheimer’s disease (AD), bipolar disorder, and rare\ndiseases like Rett syndrome. GSK-3β is also implicated in HIV-associated\ndementia (HAD), as it is upregulated in HIV-1-infected cells and plays\na role in neuronal dysfunction. Therefore, a small molecule that can\ninhibit both GSK-3β and HIV-1 reverse transcriptase could offer\nneuroprotective therapy for patients suffering from HIV-1. Despite\nthis, there are no known GSK-3β inhibitors currently approved,\nthus prompting us to screen our panel of various antiviral compounds\nagainst this kinase to better understand its structure–activity\nrelationship. We show for the first time that the approved drugs,\netravirine and rilpivirine, possess GSK-3β activity (IC<sub>50</sub> 619 nM and 502 nM, respectively). We have also identified\n3 lead molecules exhibiting IC<sub>50</sub> < 1 μM (11726169,\n12326205, and 12326207), with compound 11726169 being the most potent\nin vitro GSK-3β inhibitor (IC<sub>50</sub> = 12.1 nM). We also\ndescribe the generation of machine learning models for GSK-3β\ninhibition and their validation with our data as an external test\nset and propose their use for the future optimization of such inhibitors.