Uncovering Novel Drugs That Restore Vision By Combining Biological and Computational Drug Discovery Processes

Justine O'Brien¹, Andrea Cerquone Perpetuini², Robert Scoffin³, Breandan Kennedy^2
1UCD School of Biomolecular and Biomedical Science, ²UCD Conway Institute, UCD School of Biomolecular and Biomedical Science, ³Cresset Biomolecular Discovery Ltd

Introduction/Background & aims Inherited retinal degenerations (IRD) are a group of conditions resulting in progressive photoreceptor degeneration and blindness. Despite recent insights into the genetic and mechanistic causes of IRD, most patients still lack effective treatment. There is a pressing need for novel therapies that preserve vision. Efficient and effective screening of randomised compound libraries can facilitate identification of first in class drugs. Here, we combine biological and virtual screening processes to identify novel compounds which rescue vision in a zebrafish model of IRD.

Method/Summary of work Phenotype-based drug discovery was performed on the atp6v0e1^UCD6 zebrafish model of impaired vision screening a DIVERSet® randomised compound library. 80 drug compounds were combined into 18 orthogonal drug pools (10 µM each drug) for plate testing. Zebrafish larvae (n=5 per pool) were treated at 3 days post-fertilisation (dpf). Visual behaviour was analysed at 5 dpf by optokinetic response. Identified hits undergo iterative rounds of ligand-based computational screening to identify 3D analogues. Computational screening is performed using Cresset’s Blaze™ software. Additional triaging by 2D similarity calculations and Murcko clustering is performed using Cresset Forge™ and KNIME to shortlist candidate compounds for testing in vivo.

Results/Discussion Initial assays validated orthogonal drug pooling as an appropriate screening format. The orthogonal pooling protocol successfully detected visual rescue of atp6v0e1^UCD6 in 2 of 2 Tubastatin A spiked pools (positive control) with a 3-fold visual improvement. Orthogonal drug pooling is ongoing with 720 compounds tested to date. 86% of pools did not alter atp6v0e1 vision, 8% of pools showed overt toxicity, but 6% of pools displayed a visual improvement of ≥5 fold.

Conclusion(s) Here, we present a bespoke drug discovery workflow combining in vivo phenotype-based screening of visual behaviour cross informed with computational methods. This process successfully detects drug pools restoring vision in atp6v0e1^UCD6. Drugs identified will undergo iterative rounds of computational/ biological refinement to provide further insights into IRD mechanisms and therapeutic development.