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Inhibitor Potency (inhibitor + potency)

Distribution by Scientific Domains
Chemistry100%

Selected Abstracts

Bisubstrate Inhibitors of the Enzyme Catechol O -Methyltransferase (COMT): Efficient Inhibition Despite the Lack of a Nitro Group

CHEMBIOCHEM, Issue 9 2004
Ralph Paulini
A new generation of bisubstrate inhibitors for the S -adenosylmethionine- and magnesium ion-dependent enzyme catechol O -methyltransferase (COMT), feature binding affinities (IC50 values) in the double-digit nanomolar range despite the lack of a nitro group on the catechol moiety. Inhibitor potency does not directly correlate with the pKa value of the catechol HO groups and is strongly enhanced by hydrophobic aromatic substituents attached in a biaryl-type fashion to position 5 of the catechol ring. [source]

Effect of sequence polymorphism and drug resistance on two HIV-1 Gag processing sites

FEBS JOURNAL, Issue 16 2002
Anita Fehér
The HIV-1 proteinase (PR) has proved to be a good target for antiretroviral therapy of AIDS, and various PR inhibitors are now in clinical use. However, there is a rapid selection of viral variants bearing mutations in the proteinase that are resistant to clinical inhibitors. Drug resistance also involves mutations of the nucleocapsid/p1 and p1/p6 cleavage sites of Gag, both in vitro and in vivo. Cleavages at these sites have been shown to be rate limiting steps for polyprotein processing and viral maturation. Furthermore, these sites show significant sequence polymorphism, which also may have an impact on virion infectivity. We have studied the hydrolysis of oligopeptides representing these cleavage sites with representative mutations found as natural variations or that arise as resistant mutations. Wild-type and five drug resistant PRs with mutations within or outside the substrate binding site were tested. While the natural variations showed either increased or decreased susceptibility of peptides toward the proteinases, the resistant mutations always had a beneficial effect on catalytic efficiency. Comparison of the specificity changes obtained for the various substrates suggested that the maximization of the van der Waals contacts between substrate and PR is the major determinant of specificity: the same effect is crucial for inhibitor potency. The natural nucleocapsid/p1 and p1/p6 sites do not appear to be optimized for rapid hydrolysis. Hence, mutation of these rate limiting cleavage sites can partly compensate for the reduced catalytic activity of drug resistant mutant HIV-1 proteinases. [source]

Potency and selectivity of inhibition of cathepsin K, L and S by their respective propeptides

FEBS JOURNAL, Issue 20 2000
Jocelyne Guay
The prodomains of several cysteine proteases of the papain family have been shown to be potent inhibitors of their parent enzymes. An increased interest in cysteine proteases inhibitors has been generated with potential therapeutic targets such as cathepsin K for osteoporosis and cathepsin S for immune modulation. The propeptides of cathepsin S, L and K were expressed as glutathione S -transferase-fusion proteins in Escherichia coli. The proteins were purified on glutathione affinity columns and the glutathione S -transferase was removed by thrombin cleavage. All three propeptides were tested for inhibitor potency and found to be selective within the cathepsin L subfamily (cathepsins K, L and S) compared with cathepsin B or papain. Inhibition of cathepsin K by either procathepsin K, L or S was time-dependent and occurred by an apparent one-step mechanism. The cathepsin K propeptide had a Ki of 3.6,6.3 nm for each of the three cathepsins K, L and S. The cathepsin L propeptide was at least a 240-fold selective inhibitor of cathepsin K (Ki = 0.27 nm) and cathepsin L (Ki = 0.12 nm) compared with cathepsin S (Ki = 65 nm). Interestingly, the cathepsin S propeptide was more selective for inhibition of cathepsin L (Ki = 0.46 nm) than cathepsin S (Ki = 7.6 nm) itself or cathepsin K (Ki = 7.0 nm). This is in sharp contrast to previously published data demonstrating that the cathepsin S propeptide is equipotent for inhibition of human cathepsin S and rat and paramecium cathepsin L [Maubach, G., Schilling, K., Rommerskirch, W., Wenz, I., Schultz, J.E., Weber, E. & Wiederanders, B. (1997), Eur J. Biochem. 250, 745,750]. These results demonstrate that limited selectivity of inhibition can be measured for the procathepsins K, L and S vs. the parent enzymes, but selective inhibition vs. cathepsin B and papain was obtained. [source]

Engineering the catalytic domain of human protein tyrosine phosphatase , for structure-based drug discovery

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 12 2006
Artem G. Evdokimov
Protein tyrosine phosphatases (PTPs) play roles in many biological processes and are considered to be important targets for drug discovery. As inhibitor development has proven challenging, crystal structure-based design will be very helpful to advance inhibitor potency and selectivity. Successful application of protein crystallography to drug discovery heavily relies on high-quality crystal structures of the protein of interest complexed with pharmaceutically interesting ligands. It is very important to be able to produce protein,ligand crystals rapidly and reproducibly for as many ligands as necessary. This study details our efforts to engineer the catalytic domain of human protein tyrosine phosphatase , (HPTP,-CD) with properties suitable for rapid-turnaround crystallography. Structures of apo HPTP,-CD and its complexes with several novel small-molecule inhibitors are presented here for the first time. [source]

Ef,ciency of antidepressant drugs as monoamine reuptake inhibitors: analysis of the hydrophobicity in,uence using biopartitioning micellar chromatographic data

BIOMEDICAL CHROMATOGRAPHY, Issue 7 2004
C. Quiñones-Torrelo
Abstract The reuptake blockade of biogenic amines by antidepressants is related not only to their therapeutics effects, but also to their side effects and potential drug,drug interactions. As an alternative to classical quantitative structure,activity relationships studies, in this work we propose different quantitative retention,activity relationships (QRAR) models that are able to describe the monoamine reuptake inhibition by antidepressants. The retention of compounds is measured using a biopartitioning micellar chromatography (BMC) system that can simulate the same hydrophobic, electronic and steric molecular interactions as those that condition drug activity. Since all the compounds considered in this work are structurally related because all of them share the same molecular features as the corresponding basic pharmacophore, the results obtained show that there is a retention range in which antidepressants present the highest monoamine reuptake inhibitor potency. Copyright © 2003 John Wiley & Sons, Ltd. [source]