Enzymatic Transition States and Drug Design

Schramm, Vern L.

doi:10.1021/acs.chemrev.8b00369

Cited by 65 publications

(68 citation statements)

References 464 publications

(950 reference statements)

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“…Transition state analogues are generally efficient enzyme inhibitors, since in principle they are expected to bind more tightly to the enzyme than substrates themselves [ 186 ]. In the case of β-lactamases, a first transition state should involve the pre-formation of a tetrahedral carbon giving rise to a stable (in the case of SBLs) or high-energy (MBLs) tetrahedral intermediate.…”

Section: Mbl Inhibitors Based On Substrate Structuresmentioning

confidence: 99%

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

et al. 2020

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β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.

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Section: Mbl Inhibitors Based On Substrate Structuresmentioning

confidence: 99%

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

et al. 2020

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“…The theory of tight binding between enzymes and transition state analogs is well-established and has guided the design of many inhibitors. 25,26 The lactonization step of this reaction is particularly amenable to the design of transition state mimics. It is a 5-exo-tet cyclization, with the carboxylate displacing the sulfonium group.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Transition-State Analogs as Inhibitors of the Bacterial Quorum Sensing Autoinducer Synthase CepI

Higgins¹,

Kellner-Rogers²,

Estanislau³

et al. 2020

Preprint

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Quorum sensing is a bacterial signaling system that involves the synthesis and subsequent detection of signal molecules called autoinducers. The main autoinducer in gram-negative bacteria are acylated homoserine lactones, produced by the LuxI family of autoinducer synthase enzymes and detected by the LuxR family of autoinducer receptors. Quorum sensing allows for changes in gene expression and bacterial behaviors in a coordinated, cell density dependent manner. Quorum sensing controls the expression of virulence factors in some human pathogens, making quorum sensing an antibacterial drug target. Here we describe the design and synthesis of transition-state analogs of the autoinducer synthase enzymatic reaction and the evaluation of these compounds as inhibitors of the synthase CepI. One such compound potently inhibits CepI and constitutes a new type of inhibitor against this underdeveloped antibacterial target.

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“…Crystal structures of FCP/SCP phosphatase were solved with AlF 4 − , in which the AlF 4 − complex acts as a phosphate analogue, inducing the proposed pentacoordinate phosphorane transition state of the hydrolysis reaction [51,53]. Enzymes recognize their substrates with high affinity, as an antibody to their haptens, which have been exhibited by X-ray crystallography [55,56]. In fact, we demonstrated that the phosphatase activities of FCP/SCP family phosphatases such as Fcp1 and Scp1 were strongly inhibited by AlF 4 − .…”

Section: Scp1 Substrate Identification By Pmpd Methods With Alf 4 −mentioning

confidence: 99%

Methods for Identification of Substrates/Inhibitors of FCP/SCP Type Protein Ser/Thr Phosphatases

et al. 2020

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Protein phosphorylation is the most widespread type of post-translational modification and is properly controlled by protein kinases and phosphatases. Regarding the phosphorylation of serine (Ser) and threonine (Thr) residues, relatively few protein Ser/Thr phosphatases control the specific dephosphorylation of numerous substrates, in contrast with Ser/Thr kinases. Recently, protein Ser/Thr phosphatases were reported to have rigid substrate recognition and exert various biological functions. Therefore, identification of targeted proteins by individual protein Ser/Thr phosphatases is crucial to clarify their own biological functions. However, to date, information on the development of methods for identification of the substrates of protein Ser/Thr phosphatases remains scarce. In turn, substrate-trapping mutants are powerful tools to search the individual substrates of protein tyrosine (Tyr) phosphatases. This review focuses on the development of novel methods for the identification of Ser/Thr phosphatases, especially small C-terminal domain phosphatase 1 (Scp1), using peptide-displayed phage library with AlF4−/BeF3−, and discusses the identification of putative inhibitors.

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Enzymatic Transition States and Drug Design

Cited by 65 publications

References 464 publications

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

Design, Synthesis, and Evaluation of Transition-State Analogs as Inhibitors of the Bacterial Quorum Sensing Autoinducer Synthase CepI

Methods for Identification of Substrates/Inhibitors of FCP/SCP Type Protein Ser/Thr Phosphatases

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