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Chemically inducible systems represent valuable synthetic biology tools that enable the external control of biological processes. However, their translation to therapeutic applications has been limited because of unfavorable ligand characteristics or the immunogenicity of xenogeneic protein domains. To address these issues, we present a strategy for engineering inducible split protein regulators (INSPIRE) in which ligand-binding proteins of human origin are split into two fragments that reassemble in the presence of a cognate physiological ligand or clinically approved drug. We show that the INSPIRE platform can be used for dynamic, orthogonal and multiplex control of gene expression in mammalian cells. Furthermore, we demonstrate the functionality of a glucocorticoid-responsive INSPIRE platform in vivo and apply it for perturbing an endogenous regulatory network. INSPIRE presents a generalizable approach toward designing small-molecule responsive systems that can be implemented for the construction of new sensors, regulatory networks and therapeutic applications.

Rosemary (Rosmarinus officinalis L.) of the Lamiaceae family represents an evergreen medicinal plant with various health-promoting pharmacological effects. This paper provides a complete overview of diverse biological activities of rosemary extracts, essential oils as well as their numerous bioactive compounds, ranging from antioxidative, anti-inflammatory, and antimicrobial over cognitive enhancing to their anticarcinogenic effects. In addition, state of the art extraction, distillation, fractionation, and characterization techniques for obtaining high-quality rosemary extracts and essential oils as well as methods for determining their antioxidative, antimicrobial, anti-inflammatory, and anticarcinogenic potentials are also presented. Finally, new ideas for future computational studies on chemical reactivities and binding affinities of health-promoting rosemary compounds together with suggestions for their improved bioavailability through diverse encapsulation techniques are introduced.

Molecular dynamics (MD) and molecular docking are commonly used to study molecular interactions in drug discovery. Most docking approaches consider proteins as rigid, which can decrease the accuracy of predicted docked poses. Therefore MD simulations can be used prior to docking to add flexibility to proteins. We evaluated the contribution of using MD together with docking in a docking study on human cathepsin B, a well-studied protein involved in numerous pathological processes. Using CHARMM biomolecular simulation program and AutoDock Vina molecular docking program, we found, that short MD simulations significantly improved molecular docking. Our results, expressed with the area under the receiver operating characteristic curves, show an increase in discriminatory power i.e. the ability to discriminate active from inactive compounds of molecular docking, when docking is performed to selected snapshots from MD simulations.

We describe a novel freely available web server Base of Bioisosterically Exchangeable Replacements (BoBER), which implements an interface to a database of bioisosteric and scaffold hopping replacements. Bioisosterism and scaffold hopping are key concepts in drug design and optimization, and can be defined as replacements of biologically active compound’s fragments with other fragments to improve activity, reduce toxicity, change bioavailability or to diversify the scaffold space. Our web server enables fast and user-friendly searches for bioisosteric and scaffold replacements which were obtained by mining the whole Protein Data Bank. The working of the web server is presented on an existing MurF inhibitor as example. BoBER web server enables medicinal chemists to quickly search for and get new and unique ideas about possible bioisosteric or scaffold hopping replacements that could be used to improve hit or lead drug-like compounds.