Integrins are a family of cell surface receptors well-recognized for their therapeutic potential in a wide range of diseases. However, the development of integrin targeting medications has been impacted by unexpected downstream effects, reflecting originally unforeseen interference with the bidirectional signalling and cross-communication of integrins. We here selected one of the most severely affected target integrins, the integrin lymphocyte function-associated antigen-1 (LFA-1, αβ, CD11a/CD18), as a prototypic integrin to systematically assess and overcome these known shortcomings.
View Article and Find Full Text PDFA 4.1 μs molecular dynamics simulation of the NR4A1 (hNur77) apo-protein has been undertaken and a previously undetected druggable pocket has become apparent that is located remotely from the 'traditional' nuclear receptor ligand-binding site. A NR4A1/bis-indole ligand complex at this novel site has been found to be stable over 1 μs of simulation and to result in an interesting conformational transmission to a remote loop that has the capacity to communicate with a NBRE within a RXR-α/NR4A1 heterodimer.
View Article and Find Full Text PDFAssay Drug Dev Technol
September 2015
High-content screening (HCS) is a powerful technique for monitoring phenotypic responses to treatments on a cellular and subcellular level. Cellular phenotypes can be characterized by multivariate image readouts such as shape, intensity, or texture. The corresponding feature vectors can thus be defined as HCS fingerprints that serve as a powerful biological compound descriptor.
View Article and Find Full Text PDFis associated with inflammatory diseases and can cause gastric cancer and mucosa-associated lymphoma. One of the bacterium's key proteins is high temperature requirement A (HtrA) protein, an extracellular serine protease that cleaves E-cadherin of gastric epithelial cells, which leads to loss of cell-cell adhesion. Inhibition of HtrA may constitute an intervention strategy against infection.
View Article and Find Full Text PDFWe present the discovery of low molecular weight inhibitors of human immunodeficiency virus 1 (HIV-1) protease subtype B that were identified by structure-based virtual screening as ligands of an allosteric surface cavity. For pocket identification and prioritization, we performed a molecular dynamics simulation and observed several flexible, partially transient surface cavities. For one of these presumable ligand-binding pockets that are located in the so-called "hinge region" of the identical protease chains, we computed a receptor-derived pharmacophore model, with which we retrieved fragment-like inhibitors from a screening compound pool.
View Article and Find Full Text PDFHigh-content screening (HCS) is a powerful tool for drug discovery being capable of measuring cellular responses to chemical disturbance in a high-throughput manner. HCS provides an image-based readout of cellular phenotypes, including features such as shape, intensity, or texture in a highly multiplexed and quantitative manner. The corresponding feature vectors can be used to characterize phenotypes and are thus defined as HCS fingerprints.
View Article and Find Full Text PDFLymphangiogenesis plays an important role in promoting cancer metastasis to sentinel lymph nodes and beyond and also promotes organ transplant rejection. We used human lymphatic endothelial cells to establish a reliable three-dimensional lymphangiogenic sprouting assay with automated image acquisition and analysis for inhibitor screening. This high-content phenotype-based assay quantifies sprouts by automated fluorescence microscopy and newly developed analysis software.
View Article and Find Full Text PDFNuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidant defense systems, and activation of this transcription factor is a promising strategy for protection of skin and other organs from environmental insults. To identify efficient Nrf2 activators in keratinocytes, we combined a chemical library screen with computer-based virtual screening. Among 14 novel Nrf2 activators, the most potent compound, a nitrophenyl derivative of 2-chloro-5-nitro-N-phenyl-benzamide, was characterized with regard to its molecular mechanism of action.
View Article and Find Full Text PDFWe present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated 'in silico' assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features.
View Article and Find Full Text PDFThe periplasmic chaperone and serine protease HtrA is important for bacterial stress responses and protein quality control. Recently, we discovered that HtrA from Helicobacter pylori is secreted and cleaves E-cadherin to disrupt the epithelial barrier, but it remained unknown whether this maybe a general virulence mechanism. Here, we show that important other pathogens including enteropathogenic Escherichia coli, Shigella flexneri, and Campylobacter jejuni, but not Neisseria gonorrhoeae, cleaved E-cadherin on host cells.
View Article and Find Full Text PDFModulation of protein-protein interactions (PPI) has emerged as a new concept in rational drug design. Here, we present a computational protocol for identifying potential PPI inhibitors. Relevant regions of interfaces (epitopes) are predicted for three-dimensional protein models and serve as queries for virtual compound screening.
View Article and Find Full Text PDFVarious inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E(2) synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of the structure of 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid (1), we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition.
View Article and Find Full Text PDFBackground: De novo design of drug-like compounds with a desired pharmacological activity profile has become feasible through innovative computer algorithms. Fragment-based design and simulated chemical reactions allow for the rapid generation of candidate compounds as blueprints for organic synthesis.
Methods: We used a combination of complementary virtual-screening tools for the analysis of de novo designed compounds that were generated with the aim to inhibit inactive polo-like kinase 1 (Plk1), a target for the development of cancer therapeutics.
Patterns of receptor-ligand interaction can be conserved in functionally equivalent proteins even in the absence of sequence homology. Therefore, structural comparison of ligand-binding pockets and their pharmacophoric features allow for the characterization of so-called "orphan" proteins with known three-dimensional structure but unknown function, and predict ligand promiscuity of binding pockets. We present an algorithm for rapid pocket comparison (PoLiMorph), in which protein pockets are represented by self-organizing graphs that fill the volume of the cavity.
View Article and Find Full Text PDFRepresentation of chemical reactions is pivotal for different purposes in cheminformatics. We present an extension of the molecular query language (MQL), which combines readable style with meaningful rules for string representation of reactions and unambiguous product formation. The concept of functional groups is used to describe the transformations.
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