Structure‐Based Design of Microsomal Prostaglandin E2 Synthase‐1 (mPGES‐1) Inhibitors using a Virtual Fragment Growing Optimization Scheme

A small library of 2,3‐dihydroxybenzamide‐ and N‐(2,3‐dihydroxyphenyl)‐4‐sulfonamide‐based microsomal prostaglandin E₂ synthase‐1 (mPGES‐1) inhibitors was identified following a step‐by‐step optimization of small aromatic fragments selected to interact in focused regions in the active site of mPGES‐1. During the virtual optimization process, the 2,3‐dihydroxybenzamide moiety was first selected as a backbone of the proposed new chemical entities; the identified compounds were then synthesized and biologically evaluated, identifying derivatives with very promising inhibitory activities in the micromolar range. Subsequent structure‐guided replacement of the 2,3‐dihydroxybenzamide by the N‐(2,3‐dihydroxyphenyl)sulfonamide moiety led to the identification of N‐(2,3‐dihydroxyphenyl)‐4‐biphenylsulfonamide ( 6 ), the most potent small molecule of the series (IC₅₀=0.53±0.04 μm ). The simple synthetic procedure and the possibility of enhancing the potency of this class of inhibitors through additional structural modifications pave the way for further development of new molecules with mPGES‐1‐inhibitory activity, with potential application as anti‐inflammatory and anticancer agents.     

FRET Dyes Significantly Affect SAXS Intensities of Proteins

Structural analyses in biophysics aim at revealing a relationship between a molecule's dynamic structure and its physiological function. Förster resonance energy transfer (FRET) and small-angle X-ray scattering (SAXS) are complementary experimental approaches to this. Their concomitant application in combined studies has recently opened a lively debate on how to interpret FRET measurements in the light of SAXS data with the popular example of the radius of gyration, commonly derived from both FRET and SAXS. There still is a lack of understanding in how to mutually relate and interpret quantities equally obtained from FRET or SAXS, and to what extent FRET dyes affect SAXS intensities in combined applications. In the present work, we examine the interplay of FRET and SAXS from a computational simulation perspective. Molecular simulations are a valuable complement to experimental approaches and supply instructive information on dynamics. As FRET depends not only on the mutual separation but also on the relative orientations, the dynamics, and therefore also the shapes of the dyes, we utilize a novel method for simulating FRET-dye-labeled proteins to investigate these aspects in atomic detail. We perform structure-based simulations of four different proteins with and without dyes in both folded and unfolded conformations. In-silico derived radii of gyration are different with and without dyes and depend on the chosen dye pair. The dyes apparently influence the dynamics of unfolded systems. We find that FRET dyes attached to a protein have a significant impact on theoretical SAXS intensities calculated from simulated structures, especially for small proteins. Radii of gyration from FRET and SAXS deviate systematically, which points to further underlying mechanisms beyond prevalent explanation approaches.     

Novel experience prior to training attenuates the amnestic effects of posttraining ECS.

In this article, mice were given a novel exploratory experience 1 hr prior to training on a one-trial inhibitory avoidance task or a Y-maze shock-motivated visual discrimination task. Half of the animals in each group received immediate posttraining electroconvulsive shock (ECS) delivered through implanted cortical screws. Retention was tested 24 hr later. In the inhibitory avoidance task, retention was assessed by the response latencies on Day 2. In the Y-maze, the discrimination was reversed on Day 2 and retention of the original discrimination was assessed by errors made on six reversal training trials. Comparable results were obtained in the two tasks: ECS impaired retention in controls not given the novel experience but did not affect retention in mice given the novel experience. These findings are interpreted in terms of previous evidence, which suggests that ECS-induced amnesia may be mediated by the release of brain β-endorphin. (PsycINFO Database Record (c) 2010 APA, all rights reserved)