Publicaties

Background and purpose. CCR5 is a coreceptor for HIV-1 infection and target for anti-viral therapy. A greater understanding of the binding kinetics of small molecule allosteric ligand interaction with CCR5 will lead to a better understanding of the binding process and may help discover new molecules that avoid resistance.
Experimental approach. Using [3H] maraviroc as a radioligand, a number of different binding protocols were employed in ...

Background and purpose: Many G protein-coupled receptors (GPCRs) can be allosterically modulated by small molecule ligands. This modulation is best understood in terms of the kinetics of the ligand-receptor interaction. However, many current kinetic assays require at least the (radio-) labeling of the orthosteric ligand, which is impractical for studying a range of ligands. Here we describe the application of a so-called competition association ...

Drugs interact with proteins and that interaction leads to the pharmacological
response. The interaction involves an initial binding of the drug to the protein,
described by the second order association rate constant, k on and debinding,
described by the ?rst-order dissociation rate constant, k o? . The a?nity of the
drug for the protein is de?ned by the equilibrium dissociation constant, K d ,
which equals k o? /k on . ...

Studies in human populations and mouse models of disease have linked the common leptin receptor Q223R mutation to obesity, multiple forms of cancer, adverse drug reactions, and susceptibility to enteric and respiratory infections. Contradictory results cast doubt on the phenotypic consequences of this variant. We set out to determine whether the Q223R substitution affects leptin binding kinetics using surface plasmon resonance (SPR), a technique ...

The most successful binding kinetics analysis systems at this moment include surface plasmon resonance (SPR), quartz microcrystal balance (QMB) and surface acoustic wave (SAW). Although these are powerful methods, they generally are complex, expensive and require the use of monolayers. Here, we report on potentiometric sensors as an inexpensive and simple alternative to do binding kinetics analysis between small molecules in solution and ...

One of the major challenges in formulation development of biopharmaceuticals is improving long-term storage stability, which is often achieved by addition of excipients to the final formulation. Finding the optimal excipient for a given protein is usually done using a trial-and-error approach, due to the lack of general understanding of how excipients work for a particular protein. Previously, preferential interactions (binding or exclusion) of ...

Plant hemoglobins (Hbs) are found in nodules of legumes and actinorhizal plants but also in nonsymbiotic organs of monocots and dicots. Nonsymbiotic Hbs have been classified into two phylogenetic groups. Class 1 Hbs show an extremely high O2 affinity and are induced by hypoxia and nitric oxide (NO), whereas class 2 Hbs have moderate O2 affinity and are induced by cold and cytokinins. The functions of nonsymbiotic Hbs are still unclear, but some ...

Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification in the incretin hormone glucagon-like peptide (GLP-1) that alters the signaling capabilities of the GLP-1 receptor (GLP-1R) by making it G protein biased over internalization but was originally designed to ...

KLK4 is a serine protease from the kallikrein family that is involved in cancer progression. The diphenyl phosphonate warhead is intended to bind irreversibly with serine proteases, but unexpectedly, very potent KLK4 diphenyl phosphonate inhibitors were discovered with reversible inhibition kinetics.