Drug–target residence time: critical information for lead optimization

Lü, Hao; Tonge, Peter J.

doi:10.1016/j.cbpa.2010.06.176

Cited by 404 publications

(369 citation statements)

References 37 publications

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“…However, the residence time, which was suggested to be a particularly important kinetic quantity for the prediction of in vivo drug efficacy (34,35), increased 4-fold for TLM3 with a value of 33 min for this C171Q KasA slow onset inhibitor. Consistently, our structures also emphasize that this subset of compounds behaves differently compared with TLM5 and -6.…”

Section: Resultsmentioning

confidence: 98%

Structural Basis for the Recognition of Mycolic Acid Precursors by KasA, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis

Schiebel¹,

Kapilashrami

Fekete

et al. 2013

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 98%

Structural Basis for the Recognition of Mycolic Acid Precursors by KasA, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis

Schiebel¹,

Kapilashrami

Fekete

et al. 2013

Journal of Biological Chemistry

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“…In the context of slowly reversible inhibitors, the concept of the residence time of the inhibited target has been shown to be a key driver of pharmacokinetic-pharmacodynamic (PK-PD) relationships for enzyme targets in a wide variety of therapeutic areas (33,34). Avibactam, combined with ceftaroline or ceftazidime, has shown efficacy in preclinical animal models and also in phase II clinical trials of patients with Gram-negative infections (35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor

Ehmann

Jahić

Ross

et al. 2012

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

457

450

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Avibactam is a β-lactamase inhibitor that is in clinical development, combined with β-lactam partners, for the treatment of bacterial infections comprising Gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a β-lactam core but maintains the capacity to covalently acylate its β-lactamase targets. Using the TEM-1 enzyme, we characterized avibactam inhibition by measuring the on-rate for acylation and the offrate for deacylation. The deacylation off-rate was 0.045 min −1 , which allowed investigation of the deacylation route from TEM-1. Using NMR and MS, we showed that deacylation proceeds through regeneration of intact avibactam and not hydrolysis. Other than TEM-1, four additional clinically relevant β-lactamases were shown to release intact avibactam after being acylated. We showed that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.antibacterial | drug discovery | enzymology T here is an urgent need for new antibacterial agents that are active against drug-resistant bacteria. In particular, some Gram-negative pathogens have accumulated enough resistance mechanisms to render them virtually untreatable by modern antibacterial chemotherapy (1, 2). A mainstay for treatment of Gram-negative infections is the β-lactam classes of drugs. The most common form of resistance to β-lactam antibiotics is the expression of various β-lactamase enzymes capable of hydrolyzing the β-lactam ring of β-lactam drugs, rendering them ineffective. As new β-lactams have been introduced into clinical use, a changing landscape of β-lactamases has been selected and disseminated. Presently, over 1,000 β-lactamases have been documented comprising several structural classes and a wide range of substrate promiscuities and catalytic efficiencies (3, 4).In efforts to restore the efficacy of β-lactam antibiotics, β-lactamases have also been targeted with a variety of inhibitors (5, 6). The three inhibitors approved for clinical use are clavulanic acid, tazobactam, and sulbactam, all of which contain a β-lactam core. A challenge for the development of broad-spectrum β-lactamase inhibitors is the mechanistic diversity in β-lactamase enzymes, with the largest distinction being between the enzyme classes that use a serine residue as the nucleophilic species and the metallo-β-lactamases, which directly activate water for hydrolysis (7). A shared mechanistic feature of the marketed β-lactam-based inhibitors is their reaction with the serine enzymes to form a covalent acylenzyme intermediate. On ring opening, the acyl-enzyme intermediate can undergo additional rearrangements or be released through hydrolysis to regenerate the active β-lactamase enzyme (8). Originally designed to combat class A serine β-lactamase enzymes such as TEM-1, the clinical use of β-lactam-based inhibitors has been diminished by the emergence of enzymes against which they are ineffective. Despite intense investigation by pharmaceutical companies, no new β-lactamas...

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“…Many biochemical processes in living cells, however, occur in non-equilibrium conditions, and there has been a growing recognition that the binding rate (k 1 ) and dissociation rate (k À 1 ) of molecular interactions provide more decisive clues for understanding the cell physiology resulting from molecular interactions. For instance, the residence time of a ligand has a significant effect on the signal transduction, regulatory processes and drug responses [2][3][4][5] .…”

mentioning

confidence: 99%

Protein conformational dynamics dictate the binding affinity for a ligand

et al. 2014

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Interactions between a protein and a ligand are essential to all biological processes. Binding and dissociation are the two fundamental steps of ligand-protein interactions, and determine the binding affinity. Intrinsic conformational dynamics of proteins have been suggested to play crucial roles in ligand binding and dissociation. Here, we demonstrate how protein dynamics dictate the binding and dissociation of a ligand through a single-molecule kinetic analysis for a series of maltose-binding protein mutants that have different intrinsic conformational dynamics and dissociation constants for maltose. Our results provide direct evidence that the ligand dissociation is determined by the intrinsic opening rate of the protein.

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Drug–target residence time: critical information for lead optimization

Cited by 404 publications

References 37 publications

Structural Basis for the Recognition of Mycolic Acid Precursors by KasA, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis

Structural Basis for the Recognition of Mycolic Acid Precursors by KasA, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis

Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor

Protein conformational dynamics dictate the binding affinity for a ligand

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