A novel hypothesis-generating computational workflow utilizing reverse pharmacophore mapping-A drug repurposing...

Drug repurposing (DR) offers a compelling alternative to traditional drug discovery's lengthy, resource-intensive process. DR is the process of identifying alternative clinical applications for pre-approved drugs as a low-risk and low-cost strategy. Computational approaches are crucial during the early hypothesis-generating stage of DR. However, 'large-scale' data retrieval remains a significant challenge. A computational workflow addressing such limitations might improve hypothesis generation, ultimately benefit patients and advance DR research.

We introduce a novel computational workflow (combining free-accessible computational platforms) to provide 'proof-of-concept' of the pre-approved drug's suitability for repurposing. Three key phases are included: target fishing (via reverse pharmacophore mapping), target identification (via disease- and drug-target pathway identification) and retrospective literature and drug-like analysis (via in silico ADMET properties determination). Istradefylline is a Parkinson's disease-approved drug with literature-attributed antidepressant properties remaining unclear. Practically applied, istradefylline's antidepressant activity was assessed in the context of major depressive disorder (MDD).

Data mining aided by target identification resulted in istradefylline potentially representing a novel antidepressant drug class. Retrieved drug targets (KYNU, MAO-B, ALOX12 and PLCB2) associated with selected MDD pathways (tryptophan metabolism and serotonergic synapse) generated a hypothesis that istradefylline increased extracellular 5-HT levels (MAO-B inhibition) and reduced inflammation (KYNU, ALOX12 and PLCB2 inhibition).

The practically applied workflow's generated hypothesis aligns with known experimental data, validating the effectiveness of this novel computational workflow. It is a low-risk and low-cost DR computational tool providing a bird's-eye view for exploring alternative clinical applications of pre-approved drugs.