Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach

Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful “core hopping” and “glide docking” techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the “core hopping” technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses

Polarity Changes in the Transmembrane Domain Core of HIV-1 Vpu Inhibits Its Anti-Tetherin Activity

Tetherin (BST-2/CD317) is an interferon-inducible antiviral protein that restricts the release of enveloped viruses from infected cells. The HIV-1 accessory protein Vpu can efficiently antagonize this restriction. In this study, we analyzed mutations of the transmembrane (TM) domain of Vpu, including deletions and substitutions, to delineate amino acids important for HIV-1 viral particle release and in interactions with tetherin. The mutants had similar subcellular localization patterns with that of wild-type Vpu and were functional with respect to CD4 downregulation. We showed that the hydrophobic binding surface for tetherin lies in the core of the Vpu TM domain. Three consecutive hydrophobic isoleucine residues in the middle region of the Vpu TM domain, I15, I16 and I17, were important for stabilizing the tetherin binding interface and determining its sensitivity to tetherin. Changing the polarity of the amino acids at these positions resulted in severe impairment of Vpu-induced tetherin targeting and antagonism. Taken together, these data reveal a model of specific hydrophobic interactions between Vpu and tetherin, which can be potentially targeted in the development of novel anti-HIV-1 drugs

Identification of physical and chemical interaction mechanisms for the metals gold, silver, copper, palladium, chromium, and potassium with polyimide surfaces

In this article we briefly review the literature for the evaporated metals gold, silver, copper, palladium, chromium, and potassium on polyimide surfaces and compare these previous results to newer experiments using Fourier transform infrared reflection absorption spectroscopy (FT-IRAS) and near edge X-ray absorption fine structure spectroscopy (NEXAFS). The polyimide films were prepared by vapor phase deposition. Metal coverages range from submonolayer to several monolayers, but special emphasis in this work is put on the interaction of metals with a polyimide surface at very low metal coverages. Before our new results are presented, we discuss the various chemical and nonchemical effects, which can contribute to the change in IR absorption of polymers. For all of the metals except potassium only attenuation of polymer IR bands is observed. For the metal deposits of Au, Cu, Ag, and Pd the attenuation of the IR bands can be explained by a purely physical interaction mechanism, i.e., dynamical dipole screening and changes in the intermolecular dipole−dipole coupling between the polymer macromolecules. Deposition of potassium leads to very different and characteristic changes of the polymer IR bands and of the NEXAFS spectra which can conclusively be explained with an electron transfer from the potassium onto the polyimide. In the case of chromium the IR and NEXAFS data indicate that the chemical and physical interaction of chromium with polyimide is very complex already at the initial stage of the metal/polymer interface formation and cannot be explained conclusively with any of the interaction models suggested in the literature