FSP-3

To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50= 0.0021 μM), 1.7-fold (K103N, EC50= 0.0019 μM), and slightly more potent (E138K, EC50= 0.0075 μM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC50= 18.52 μM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp3(Fraction of sp3carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.

The drug-likeness of a compound is a key factor during the initial phases of drug discovery. It can be defined as the similarity between compounds and drugs. Here, we collate research related to the fraction of sp3carbon atoms (Fsp3), including related high-throughput screening (HTS) cases, structural modifications based on Fsp3, and strategies to improve it. We also introduce new synthetic methods for spirocyclic scaffolds. It is likely that the reasonable rigidity of spirocyclic scaffolds will provide a new generation of drug candidates.

Fragment-based drug discovery (FBDD) is a popular method in academia and the pharmaceutical industry for the discovery of early lead candidates. Despite its wide-spread use, the approach still suffers from laborious screening workflows and a limited diversity in the fragments applied. Presented here is the design, synthesis, and biological evaluation of the first fragment library specifically tailored to tackle both these challenges. The 3F library of 115 fluorinated, Fsp3-rich fragments is shape diverse and natural-product-like with desirable physicochemical properties. The library is perfectly suited for rapid and efficient screening by NMR spectroscopy in a two-stage workflow of19F NMR and subsequent1H NMR methods. Hits against four diverse protein targets are widely distributed among the fragment scaffolds in the 3F library and a 67 % validation rate was achieved using secondary assays. This collection is the first synthetic fragment library tailor-made for19F NMR screening and the results demonstrate that the approach should find broad application in the FBDD community.