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

摘要: Accelerated development of lead structures is high interest to the pharmaceutical industry in order decrease times and costs. We showcase how an intelligent combination AI-based drug screening with state-of-the-art biophysics drives rapid identification novel inhibitor chemical diversity for cGMP-dependent 39,59-cyclic phosphodiesterase (PDE2). The starting point was off-the-shelve library two million drug-like compounds. In a single silico reduction step, we short-listed 125 compounds - focused as potential binders PDE2 tested their binding behavior vitro using MicroScale Thermophoresis (MST). Of this library, seven indicated PDE2, translating hit rate 6%. Three these have affinities lower micromolar range. compound highest affinity showed KD 10μM thus excellent further medicinal chemistry optimization. results show innovative structure-driven approaches can be used accelerate discovery obtain new molecular scaffolds at fraction costs time compared standard high-throughput screening.