Uncovering novel drugs that restore vision by combining biological and computational drug discovery processes

Abstract

Purpose : Inherited retinal diseases (IRD) are a group of conditions with progressive photoreceptor or RPE dysfunction resulting in blindness. Most IRDs lack effective treatments and novel therapies are needed to preserve vision. Phenotype-based screening of randomised compound libraries enables unbiased 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.

Methods : Phenotype-based drug discovery was performed on the atp6v0e1^UCD6 zebrafish model of impaired vision screening a DIVERSet-Exp MF6 randomised compound library. 80 drug compounds were combined into 18 orthogonal drug pools for each plate testing. Visual behaviour was analysed at 5 days post-fertilisation by optokinetic response. Identified hits undergo iterative rounds of ligand-based computational screening to identify 3D analogues. A proof-of-concept virtual screen to identify mimetics of known neuroprotectant 7,8-dihydroxyflavone (7,8-DHF) was performed using Cresset Blaze™ software. Additional triaging was performed using Cresset Forge™ and KNIME.

Results : The orthogonal pooling protocol successfully detected visual rescue of atp6v0e1^UCD6 in tubastatin A spiked pools (positive control) with 3-fold visual improvement and no toxicity in 10 µM pools of each drug. Orthogonal drug pooling is ongoing with 480 compounds tested to date. 7.4% of drug pools display a visual improvement of ≥4 fold with a toxicity level of 3.7%. An initial raw list of 2,000 molecules from a database of 16 million compounds was obtained from the Blaze™ screen. Manual analysis by 2D similarity calculations and murcko clustering shortlisted a final 25 compounds for biological validation.

Conclusions : 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 pools and single drugs 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.

This is a 2021 ARVO Annual Meeting abstract.