Quantitative measures of molecular similarity: Methods to analyze transition-state analogs for enzymatic reactions

Bagdassarian, Carey K.; Braunheim, Benjamin B.; Schramm, Vern L.; Schwartz, Steven D.

doi:10.1002/(sici)1097-461x(1996)60:8<1797::aid-qua7>3.0.co;2-t

Cited by 8 publications

(4 citation statements)

References 18 publications

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“…Similarity between Substrate , Inhibitors , and Transition State . The similarities of substrate and inhibitor to the transition state were determined with a similarity measure sensitive both to the electrostatic potential distribution on the molecular surfaces and to the surface geometries ( , ). The electron density and molecular electrostatic potentials of the molecules are calculated from ab initio techniques using Gaussian 94 ().…”

Section: Methodsmentioning

confidence: 99%

One-Third-the-Sites Transition-State Inhibitors for Purine Nucleoside Phosphorylase

et al. 1998

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Genetic defects in human purine nucleoside phosphorylase cause T-cell deficiency as the major phenotype. It has been proposed that efficient inhibitors of the enzyme might intervene in disorders of T-cell function. Compounds with features of the transition-state structure of purine nucleoside phosphorylase were synthesized and tested as inhibitors. The transition-state structure for purine nucleoside phosphorylase is characterized by (1) an elevated pKa at N7 of the purine ring for protonation or favorable H-bond interaction with the enzyme and (2) oxocarbenium ion formation in the ribosyl ring (Kline, P. C., and Schramm, V. L. (1995) Biochemistry 34, 1153-1162). Both features have been incorporated into the stable transition-state analogues, (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (immucillin-H) and (1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1, 4-imino-D-ribitol (immucillin-G). Both inhibitors exhibit slow-onset tight-binding inhibition of calf spleen and human erythrocyte purine nucleoside phosphorylase. The inhibitors exhibit equilibrium dissociation constants (Ki) from 23 to 72 pM and are the most powerful inhibitors reported for the enzyme. Complete inhibition of the homotrimeric enzyme occurs at one mole of inhibitor per mole of enzymic trimer. Binding of the transition-state inhibitor at one site per trimer prevents inhibitor binding at the remaining two sites of the homotrimer. A mechanism of sequential catalysis at each subunit, similar to that of F1 ATPase, is supported by these results. Slow inhibitor dissociation (e.g., t1/2 of 4.8 h) suggests that these compounds will have favorable pharmacologic properties. Interaction of transition-state inhibitors with purine nucleoside phosphorylase is different from reactant-state (substrate and product analogue) inhibitors of the enzyme which bind equally to all subunits of the homotrimer.

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Section: Methodsmentioning

confidence: 99%

One-Third-the-Sites Transition-State Inhibitors for Purine Nucleoside Phosphorylase

et al. 1998

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“…One method ranks the similarity of proposed analogs by parameters of geometry and electrostatic potential surface against the same parameters for transition-state analogs (53, 54). As geometry and electrostatics are the dominant parameters for ligand recognition, molecules more similar to the transition state are bound more tightly.…”

Section: Design Of Transition-state Analogsmentioning

confidence: 99%

Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes

Schramm

2011

Annu. Rev. Biochem.

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Experimental analysis of enzymatic transition-state structures uses kinetic isotope effects (KIEs) to report on bonding and geometry differences between reactants and the transition state. Computational correlation of experimental values with chemical models permits three-dimensional geometric and electrostatic assignment of transition states formed at enzymatic catalytic sites. The combination of experimental and computational access to transition-state information permits (a) the design of transition-state analogs as powerful enzymatic inhibitors, (b) exploration of protein features linked to transition-state structure, (c) analysis of ensemble atomic motions involved in achieving the transition state, (d) transition-state lifetimes, and (e) separation of ground-state (Michaelis complexes) from transition-state effects. Transition-state analogs with picomolar dissociation constants have been achieved for several enzymatic targets. Transition states of closely related isozymes indicate that the protein’s dynamic architecture is linked to transition-state structure. Fast dynamic motions in catalytic sites are linked to transition-state generation. Enzymatic transition states have lifetimes of femtoseconds, the lifetime of bond vibrations. Binding isotope effects (BIEs) reveal relative reactant and transition-state analog binding distortion for comparison with actual transition states.

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“…Bagdassarian et al (114,115) examined this relationship using three enzymes for which the transition state structures had been characterized by kinetic isotope effects. AMP deaminase, adenosine deaminase, and AMP nucleosidase were considered by comparing the geometric and molecular electrostatic potential surfaces of the experimentally determined transition states with the substrates and a series of inhibitors exhibiting classic competitive inhibition and slowonset, tight-binding inhibition (e.g.…”

Section: Prediction Of Inhibitory Strengthmentioning

confidence: 99%

Enzymatic Transition States and Transition State Analog Design

Schramm

1998

Annu. Rev. Biochem.

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273

264

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All chemical transformations pass through an unstable structure called the transition state, which is poised between the chemical structures of the substrates and products. The transition states for chemical reactions are proposed to have lifetimes near 10 −13 sec, the time for a single bond vibration. No physical or spectroscopic method is available to directly observe the structure of the transition state for enzymatic reactions. Yet transition state structure is central to understanding catalysis, because enzymes function by lowering activation energy. An accepted view of enzymatic catalysis is tight binding to the unstable transition state structure. Transition state mimics bind tightly to enzymes by capturing a fraction of the binding energy for the transition state species. The identification of numerous transition state inhibitors supports the transition state stabilization hypothesis for enzymatic catalysis. Advances in methods for measuring and interpreting kinetic isotope effects and advances in computational chemistry have provided an experimental route to understand transition state structure. Systematic analysis of intrinsic kinetic isotope effects provides geometric and electronic structure for enzyme-bound transition states. This information has been used to compare transition states for chemical and enzymatic reactions; determine whether enzymatic activators alter transition state structure; design transition state inhibitors; and provide the basis for predicting the affinity of enzymatic inhibitors. Enzymatic transition states provide an understanding of catalysis and permit the design of transition state inhibitors. This article reviews transition state theory for enzymatic reactions. Selected examples of enzymatic transition states are compared to the respective transition state inhibitors.

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Quantitative measures of molecular similarity: Methods to analyze transition-state analogs for enzymatic reactions

Cited by 8 publications

References 18 publications

One-Third-the-Sites Transition-State Inhibitors for Purine Nucleoside Phosphorylase

One-Third-the-Sites Transition-State Inhibitors for Purine Nucleoside Phosphorylase

Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes

Enzymatic Transition States and Transition State Analog Design

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