Quantum mechanics-driven structure-activity relationship study of PEX5-PEX14 protein-protein interaction inhibitors based on a dibenzo[b,e]azepin-6(6H)-one scaffold

Targeting protein-protein interactions (PPIs) is a promising strategy in drug development. However, despite the considerable progress in the field, targeting PPIs with small molecules remains challenging, requiring novel strategies in inhibitor design and subsequent structure-activity relationship (SAR) studies. We have recently identified the PEX5-PEX14 PPI as a novel therapeutic target against diseases related to Trypanosoma infections and discovered small-molecule inhibitors against PEX14 using structure-based drug discovery (SBDD). The current study demonstrates that combining SBDD with quantum mechanical (QM) energy decomposition and deconvolution analysis (EDDA) provides an in-depth understanding of SAR in the newly developed PPI inhibitors class. We obtained diverse dibenzo[b,e]azepin-6(6H)-one PEX14 inhibitors, which resulted from redesigning the central scaffold of one of the previous compound lines and follow-up modifications. The diversification strategy yielded compounds obtained by multicomponent reactions (MCRs), from which the Kabachnik-Fields reaction products were the most potent tricyclic PEX5-PEX14 PPI inhibitors obtained so far. Overall, the activities of the compounds measured with biophysical assays aligned with the QM-derived compound binding energies. Hence, using an advanced computational approach, our results pave an alternative way for SAR rationalization of compounds against PPI targets.