Discovering Potent Small Molecule Inhibitors of Cyclophilin A Using de Novo Drug Design Approach

This work describes an integrated approach of de novo drug design, chemical synthesis, and bioassay for quick identification of a series of novel small molecule cyclophilin A (CypA) inhibitors (1−3). The activities of the two most potent CypA inhibitors (3h and 3i) are 2.59 and 1.52 nM, respectively, which are about 16 and 27 times more potent than that of cyclosporin A. This study clearly demonstrates the power of our de novo drug design strategy and the related program LigBuilder 2.0 in drug discovery.