A platform for target prediction of phenotypic screening hit molecules

Nadine Homeyer,Ruud Van Deursen,Bernardo Ochoa-Montaño,Kathrin Heikamp,Peter Ray,Fabio Zuccotto,Tom L Blundell,Ian H Gilbert

doi:10.1016/j.jmgm.2019.107485

Nadine Homeyer, Ruud Van Deursen + Show 6 more

Open Access

https://doi.org/10.1016/j.jmgm.2019.107485

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Abstract

Many drug discovery programmes, particularly for infectious diseases, are conducted phenotypically. Identifying the targets of phenotypic screening hits experimentally can be complex, time-consuming, and expensive. However, it would be valuable to know what the molecular target(s) is, as knowledge of the binding pose of the hit molecule in the binding site can facilitate the compound optimisation. Furthermore, knowing the target would allow de-prioritisation of less attractive chemical series or molecular targets. To generate target-hypotheses for phenotypic active compounds, an in silico platform was developed that utilises both ligand and protein-structure information to generate a ranked set of predicted molecular targets. As a result of the web-based workflow the user obtains a set of 3D structures of the predicted targets with the active molecule bound. The platform was exemplified using Mycobacterium tuberculosis, the causative organism of tuberculosis. In a test that we performed, the platform was able to predict the targets of 60% of compounds investigated, where there was some similarity to a ligand in the protein database.

Highlights

Phenotypic drug discovery is a powerful way to conduct drug discovery programmes [1,2], in the area of infectious diseases, where there are very few well-validated molecular targets
These compounds have the correct properties for permeation through the cellular envelope, are metabolically stable in the infectious organism and access the molecular target(s) without significant efflux, which is a major problem in certain disease areas such as tuberculosis (TB) and Gram-negative bacteria
No target could be predicted in 16 cases, because there were no ligands or fragments present in the Protein Databank (PDB) database that were sufficiently similar to the analyzed TIBLE ligands

Summary

Introduction

Phenotypic drug discovery is a powerful way to conduct drug discovery programmes [1,2], in the area of infectious diseases, where there are very few well-validated molecular targets. The advantage of phenotypic screening is that compounds that are active in phenotypic screening modulate a mechanism(s) or pathway that is essential for the survival of the organism. These compounds have the correct properties for permeation through the cellular envelope, are metabolically stable in the infectious organism and access the molecular target(s) without significant efflux, which is a major problem in certain disease areas such as tuberculosis (TB) and Gram-negative bacteria. Often target-based approaches fail due to low intracellular compound levels

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