Publisher Summary This chapter discusses Raster3D, which is a suite of programs for molecular graphics. Crystallographers were among the first and most avid consumers of graphics workstations. Rapid advances in computer hardware, and particularly in the power of specialized computer graphics boards, have led to successive generations of personal workstations with ever more impressive capabilities for interactive molecular graphics. For many years, it was standard practice in crystallography laboratories to prepare figures by photographing directly from the workstation screen. No matter how beautiful the image on the screen, however, this approach suffers from several intrinsic limitations. Among these is the inherent limitation imposed by the effective resolution of the screen. Use of the graphics hardware in a workstation to generate images for later presentation can also impose other limitations. Designers of workstation hardware must compromise the quality of rendered images to achieve rendering speeds high enough for useful interactive manipulation of three-dimensional objects.

Raster3D: photorealistic molecular graphics.

Epidemiological data and in vitro studies on cancer chemoprevention by tea polyphenols have gained attention recently from the scientific community, nutritionists, the pharmaceutical industry, and the public. Despite the several efforts made recently to elucidate the molecular basis for the anticancer activity of these natural products, little correlation has been found thus far between the putative protein targets of compounds found in tea extracts and levels found in plasma after tea consumption. Here, by using a combination of nuclear magnetic resonance binding assays, fluorescence polarization assay, and computational docking studies, we found that certain green tea catechins and black tea theaflavins are very potent inhibitors (K(i) in the nanomolar range) of the antiapoptotic Bcl-2-family proteins, Bcl-x(L) and Bcl-2. These data suggest a strong link between the anticancer activities of these tea polyphenols and their inhibition of a crucial antiapoptotic pathway, which is implicated in the development of many human malignancies.

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Cancer Prevention by Tea Polyphenols Is Linked to Their Direct Inhibition of Antiapoptotic Bcl-2-Family Proteins

JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo, BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.

https://www.pnas.org/content/pnas/105/43/16809.full.pdf

Identification of a new JNK inhibitor targeting the JNK-JIP interaction site

Two polymorphs of amylose, the native double-helical A-form and the single-stranded V H counterpart, as well as the amylose polyiodide complex were subjected to a molecular modeling study. Based on their X-ray diffraction-derived structures, the solvent-accessible' contact surfaces were generated, onto which the computed molecular lipophilicity profiles (MLPs) were projected in color-coded form, easily allowing to locate hydrophobic and hydrophilic surface regions. Their detailed analysis revealed the double-stranded A-form to be a rather compact structure with an irregular distribution of hydrophilic and hydrophobic regions over the entire outer surface, with the interior of the double helix being inaccessible even for small molecules. By contrast, V H -amylose, in accord with its water solubility, has a pronouncedly hydrophilic outside surface with an as distinctly hydrophobic channel. - In the dark-blue amylose-polyiodide complex, the hydrophobic channel of the single-helical V H -form serves as a well-ordered matrix for incorporation and alignment of the iodine-iodide species to elaborate a linear polyiodide chain in a nearly perfect steric fit and in full complementarity of hydrophobic regions of guest and host. Thus, the MLPs provide substantive credence to the view, that not only the amylose-iodine complex formation is mediated to an essential degree by hydrophobic attractions at the guest-host interface, but that the same factors determine the stability of this unique supramolecular assembly.

Stefan Reiling

Papers

Texture mapping: A new tool for molecular graphics