Biochemical mechanisms of drug action: what does it take for success?

Swinney, David C.

doi:10.1038/nrd1500

Cited by 375 publications

(345 citation statements)

References 54 publications

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“…In contrast to a conventional inhibitor that forms only a rapidly dissociating enzyme:inhibitor (EI) complex, a two-step time-dependent inhibitor rapidly forms an encounter (EI) complex, followed by a slow isomerization to a terminal complex (EI*, Scheme 1) (9-11). Because a slow tight-binding inhibitor frequently resides on its target enzyme with a longer half-life than a conventional inhibitor, even when substrate accumulates, slow-binding inhibitors are highly desirable (12).…”

mentioning

confidence: 99%

Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding

Barb

Jiang

Raetz

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

125

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The UDP-3- O -( R -3-hydroxyacyl)- N -acetylglucosamine deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising antibiotic target. CHIR-090, the most potent LpxC inhibitor discovered to date, displays two-step time-dependent inhibition and kills a wide range of Gram-negative pathogens as effectively as ciprofloxacin or tobramycin. In this study, we report the solution structure of the LpxC–CHIR-090 complex. CHIR-090 exploits conserved features of LpxC that are critical for catalysis, including the hydrophobic passage and essential active-site residues. CHIR-090 is adjacent to, but does not occupy, the UDP-binding pocket of LpxC, suggesting that a fragment-based approach may facilitate further optimization of LpxC inhibitors. Additionally, we identified key residues in the Insert II hydrophobic passage that modulate time-dependent inhibition and CHIR-090 resistance. CHIR-090 shares a similar, although previously unrecognized, chemical scaffold with other small-molecule antibiotics such as L-161,240 targeting LpxC, and provides a template for understanding the binding mode of these inhibitors. Consistent with this model, we provide evidence that L-161,240 also occupies the hydrophobic passage.

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mentioning

confidence: 99%

Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding

Barb

Jiang

Raetz

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

125

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“…NBI-74330 appears to be selective for CXCR3 because it did not affect chemotactic responses by the human H9 T lymphoma cell line in response to CXCL12 and CCL19, and it did not interfere with calcium mobilization induced by lysophosphatidic acid or radioligand specific binding to several nonchemokine GPCRs. (Swinney, 2004). That is, if the dissociation rate of NBI-74330 was significantly longer than that of CXCL11 in assays that are not measured at equilibrium (i.e., [ 35 S]GTP␥S exchange and calcium mobilization assays), then antagonist-occupied receptors would be functionally removed from the receptor population long enough to allow for the appearance of insurmountable antagonist activity.…”

Section: Cxcr3 Ligand and Antagonist Pharmacology 1269mentioning

confidence: 99%

Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

Heise¹,

Pahuja²,

Hudson³

et al. 2005

J Pharmacol Exp Ther

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The CXC chemokine receptor 3 (CXCR3) is predominantly expressed on T helper type 1 (Th1) cells that are involved in inflammatory diseases. The three CXCR3 ligands CXCL9, CXCL10, and CXCL11 are produced at sites of inflammation and elicit migration of pathological Th1 cells. Here, we are the first to characterize the pharmacological potencies and specificity of a CXCR3 antagonist, N-1R- [3-(4-ethoxy-phenyl of 7 to 18 nM). NBI-74330 was selective for CXCR3 because it showed no significant inhibition of chemotactic responses to other chemokines and did not inhibit radioligand binding to a panel of nonchemokine G-protein coupled receptors. There was a striking difference in potencies among the three CXCR3 ligands, with CXCL11 Ͼ Ͼ CXCL10 Ͼ CXCL9. A comparison of the rank order of K i values with the rank order of monocyte production levels of these three ligands revealed a precise inverse correlation, suggesting that the weaker receptor affinities of CXCL9 and CXCL10 were physiologically compensated for by an elevated expression, perhaps to maintain effectiveness of each ligand under physiological conditions.

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“…In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times.…”

Section: Introductionmentioning

confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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Biochemical mechanisms of drug action: what does it take for success?

Cited by 375 publications

References 54 publications

Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding

Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding

Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

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