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bioRxiv · 10.1101/2020.04.22.021360

Focus Your Screening Library: Rapid Identification of Novel PDE2 Inhibitors with in silico Driven Library Prioritization and MicroScale Thermophoresis

Kaiser, F.·Plach, M. G.·Schubert, T.·Haupt, V. J.
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Abstract

Accelerated development of lead structures is of high interest to the pharmaceutical industry in order to decrease development times and costs. We showcase how an intelligent combination of AI-based drug screening with state-of-the-art biophysics drives the rapid identification of novel inhibitor structures with high chemical diversity for cGMP-dependent 3,5-cyclic phosphodiesterase (PDE2). The starting point was an off-the-shelve chemical library of two million drug-like compounds. In a single in silico reduction step, we short-listed 125 compounds - the focused library - as potential binders to PDE2 and tested their binding behavior in vitro using MicroScale Thermophoresis (MST). Of this focused library, seven compounds indicated binding to PDE2, translating to a hit rate of 6%. Three of these compounds have affinities in the lower micromolar range. The compound with the highest affinity showed a KD of 10 {micro}M and is thus an excellent starting point for further medicinal chemistry optimization. The results show how innovative and structure-driven in silico approaches and biophysics can be used to accelerate drug discovery and to obtain new molecular scaffolds at a fraction of the costs and time - compared with standard high-throughput screening.

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Kaiser, F., Plach, M. G., Schubert, T., Haupt, V. J.. 2020-04-23. Focus Your Screening Library: Rapid Identification of Novel PDE2 Inhibitors with in silico Driven Library Prioritization and MicroScale Thermophoresis. https://doi.org/10.1101/2020.04.22.021360

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