Discovering novel chemical inhibitors of human cyclophilin A: Virtual screening, synthesis, and bioassay

Abstract Cyclophilin A (CypA) is a member of cyclophilins, a family of the highly homologous peptidyl prolyl cis–trans isomerases (PPIases), which can bind to cyclosporin A (CsA). CypA plays critical roles in various biological processes, including protein folding, assembly, transportation, regulation of neuron growth, and HIV replication. The discovery of CypA inhibitor is now of a great special interest in the treatment of immunological disorders. In this study, a series of novel small molecular CypA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. The SPECS_1 database containing 85,000 small molecular compounds was searched by virtual screening against the crystal structure of human CypA. After SPR-based binding affinity assay, 15 compounds were found to show binding affinities to CypA at submicro-molar or micro-molar level (compounds 1 – 15 ). Seven compounds were selected as the starting point for the further structure modification in considering binding activity, synthesis difficulty, and structure similarity. We thus synthesized 40 new small molecular compounds ( 1 – 6 , 15 , 16a – q , 17a – d , and 18a – l ), and four of which (compounds 16b , 16h , 16k , and 18g ) showed high CypA PPIase inhibition activities with IC 50 s of 2.5–6.2 μM. Pharmacological assay indicated that these four compounds demonstrated somewhat inhibition activities against the proliferation of spleen cells.