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Topic:  Drug screening

Speaker: Aurora Martinez and Gloria Gamiz from Neuro-SysMed's Drug Discovery Node

Title:ÌýScreening and development of drugs for neurological targets

Place: The auditorium in Armauer Hansens Hus (campus Haukeland University Hospital, Bergen)

Time: Wednesday May 21, 2025, at 11:30–13:00 (lunch 11:30–12:00).

Registration: please

Langage: English

Abstract: The discovery of drugs for neurological targets typically begins with precise target identification and validation, followed by robust screening strategies. High-throughput screening (HTS) of large compound libraries, including approved drugs, is performed with subsequent validation in cellular assays using disease-relevant cells. For unknown or complex targets, phenotypic screening  assays can also be employed. Structural understanding of the target aids in preclinical hit-to-lead optimization, leading to the nomination of effective and safe candidates for clinical trials. As an example, we will present a screening campaign that identified a non-steroidal anti-inflammatory drug as a stabilizer of tyrosine hydroxylase (TH), the enzyme crucial for dopamine synthesis. The identified drug showed high binding affinity and significant stabilizing effects on TH and a genetic variant causing TH deficiency (THD), a rare disorder associated with reduced dopamine and symptoms ranging from dystonia to parkinsonism. Efficient therapeutic alternatives to levodopa are urgently needed for THD. In silico docking, molecular dynamics simulations, analogue testing, and site-directed mutagenesis revealed the drug's binding site, offering potential for further optimization. Critical considerations such as blood-brain barrier permeability and neurotoxicity also guide the preclinical development of drugs for neurological targets.