Strategy for Discovering Chemical Inhibitors of Human Cyclophilin A:  Focused Library Design, Virtual Screening, Chemical Synthesis and Bioassay

Abstract

The discovery of cyclophilin A (CypA) inhibitor is now of special interest in the treatment of immunological disorders. In this work, using a strategy integrating focused combinatorial library design, virtual screening, chemical synthesis, and bioassay, a series of novel small molecular CypA inhibitors have been discovered. First, using the fragments taken from our previously discovered CypA inhibitors (Bioorg. Med. Chem. 2006, 14, 2209-2224) as building blocks, we designed a focused combinatorial library containing 255 molecules employing the LD1.0 program (J. Comb. Chem. 2005, 7, 398-406) developed by us. Sixteen compounds (1a-e, 2a-b, 3a-b, and 4a-g) were selected by using virtual screening against the X-ray crystal structure of CypA as well as druglike analysis for further synthesis and bioassay. All these sixteen molecules are CypA binders with binding affinities (K(D) values) ranging from 0.076 to 41.0 microM, and five of them (4a, 4c, and 4e-g) are potent CypA inhibitors with PPIase inhibitory activities (IC(50) values) of 0.25-6.43 microM. The hit rates for binders and inhibitors are as high as 100% and 31.25%, respectively. Remarkably, both the binding affinity and inhibitory activity of the most potent compound increase approximately 10 times than that of the most active compound discovered previously. The high hit rate and the high potency of the new CypA inhibitors demonstrated the efficiency of the strategy for focused library design and screening. In addition, the novel chemical entities reported in this study could be leads for discovering new therapies against the CypA pathway.

Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans

“…The calculated physicochemical properties of synazo-1 were compared with typical ranges for lead-like molecules. [73–75] Synazo-1 flags just one of the common warnings for drug lead-like properties (Table 4) — molecular weight. For comparison, the orally available azole posoconazole is outside the range on four of the parameters.…”

Design, synthesis, and biological evaluation of thieno[3,2‐d]pyrimidine derivatives as potential simplified phosphatidylinositol 3‐kinase alpha inhibitors

“…The plate was then sealed and incubated at room temperature overnight (Han et al., ). The intensity of the light emission was measured by an EnVision Multilabel Reader (PerkinElmer) in TR‐FRET mode (excitation at 320 nM and emission at 665 nM) (Li et al., ). The IC 50 values were calculated by fitting data to a logistic curve using GraphPad Prism 6 software (Jiang et al., ).…”

iDrug: a web-accessible and interactive drug discovery and design platform

“…Li et al . customized LigBuilder 2.0 to generate and fit the shape of the Cyclophilin A (CypA) binding site and finally obtained two highly potent inhibitors with nanomolar inhibitory potencies (2.59 nM and 1.52 nM) [34]. A receptor-based pharmacophore modeling program Pocket v.2 was used to extract pharmacophore features within cavities [21].…”