Refinement and 3D‐QSAR Studies of Inhibitors of Cyclophilin A Containing Amide Linker

Abstract

Cyclophilin A (CypA) is a ubiquitous cellular enzyme playing essential role in many biological processes, and the discovery of CypA inhibitor is now of special interest in the treatment of immunological disorders. In this work, molecular modeling studies were performed to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in 3D‐QSAR studies using CoMFA and CoMSIA. A total of 30 compounds containing an amide fragment as the key linker, consisting of 17 of our previously discovered CypA inhibitors and 13 other inhibitors reported in the literature, were selected for pharmacophore refinement and 3D‐QSAR studies. The best pharmacophore hypothesis AADR, which had two hydrogen bond acceptors, a hydrogen bond donor, and an aromatic ring, was obtained and used for the alignment of molecules in CoMFA and CoMSIA model development. The models showed a good r 2 value of 0.992 and 0.949 for CoMFA and CoMSIA, respectively. The contour maps of the models were analyzed to give structural insight for activity improvement of future novel CypA inhibitors. The CPH can also provide a powerful template for virtual screening and design of new CypA inhibitors.