Increasing insight into the area of molecular cancer biology and structural biology has resulted in the disclosure of an increasing number of chemopreventive targets, which can be exploited for rapid rational discovery of chemopreventive agents. In this article, we discuss the application of in silicon approaches including molecular docking, pharmacophore modeling, fragment-based drug design, homology modeling, and target prediction in facilitating the search and designing of chemopreventive agents. These computational strategies have shown promising potential in speeding drug discovery and is expected to contribute to intelligent chemopreventive agents.

•Nitrendipine amorphous solid dispersions named TDP-PVP and TDP-PEG were prepared.•Hydrogen bond forces were formed between drug and excipient in TDP-PVP and TDP-PEG.•Fit profile of contact angle to get dissolution mechanism of TDP-PVP and TDP-PEG.•TDP-PEG was carrier-controlled and TDP-PVP was drug/carrier-controlled diffusion.Herein, interfacial interactions of amorphous solid dispersion formed by nitrendipine (TDP) and two types of water-soluble polymers (polyvinyl pyrrolidone K30 (PVP) and polyethylene glycol 6000 (PEG)) were tracked mainly concerning with interaction forces and wetting process. Infrared spectroscopy (IR), raman spectroscopy and contact angle instrument were mainly used through the study. Hydrogen bonding forces were formed between drug and excipient in TDP-PVP and TDP-PEG. The red raman shift of TDP-PVP and TDP-PEG confirmed the hydrogen bonding forces between TDP and the two polymers. Both TDP-PVP and TDP-PEG showed higher drug release and TDP-PVP accomplished TDP release faster due to its better drug amorphous state. It is believed that the track of interfacial interactions will certainly become powerful tools to provide valuable instruction for designing and evaluating amorphous solid dispersions.Download high-res image (142KB)Download full-size image

A structure-based virtual screening approach to targeting p21-activated kinase 4 (PAK4) was performed to identify good chemical starting points for medicinal chemistry. A pre-filtrated database was screened against two designed PAK4 pharmacophores, and the pharmacophore search hits were docked into a PAK4 crystal structure. Twenty-seven compounds were then selected for in vitro PAK4 inhibition assay, and results showed three compounds exhibiting a micro-molar IC50 in a dose–response assay. Interactive modes of the three compounds were studied and showed good binding modes in the PAK4 active site. Calculated ADME/T properties of the three hits were also analyzed and showed good drug-like properties. The results of in vitro PAK4 inhibition assay, interactive mode study and ADME/T prediction revealed that the three compounds have potential PAK4 inhibitory activities and can be further optimized and developed as lead compounds.