Transition state analog

For other types of analogs, see Analog (disambiguation).

Transition state analogs (transition state analogues), are chemical compounds with a chemical structure that resembles the transition state of a substrate molecule in an enzyme-catalyzed chemical reaction. Enzymes interact with a substrate by means of strain or distortions, moving the substrate towards the transition state.[1] Theory suggests that enzyme inhibitors which resembled the transition state structure would bind more tightly to the enzyme than the actual substrate.[2] Transition state analogs can be used as inhibitors in enzyme-catalyzed reactions by blocking the active site of the enzyme. Examples of drugs that are transition state analog inhibitors include flu medications such as the neuraminidase inhibitor oseltamivir and the HIV protease inhibitors saquinavir in the treatment of AIDS.

Transition state analogue

The transition state of a structure can best be described in regards to statistical mechanics where the energies of bonds breaking and forming have an equal probability of moving from the transition state backwards to the reactants or forward to the products. In enzyme-catalyzed reactions, the overall activation energy of the reaction is lowered when an enzyme stabilizes a high energy transition state intermediate. Transition state analogs mimic this high energy intermediate but do not undergo a catalyzed chemical reaction and can therefore bind much stronger to an enzyme than simple substrate or product analogs.

Designing transition state analogue

To design a transition state analogue, the pivotal step is the determination of transition state structure of substrate on the specific enzyme of interest with experimental method, for example, kinetic isotope effect. In addition, the transition state structure can also be predicted with computational approaches as a complementary to KIE. We will explain these two methods in brief.

Kinetic isotope effect

Kinetic isotope effect (KIE) is a measurement of the reaction rate of isotope-labeled reactants against the more common natural substrate. Kinetic isotope effect values are a ratio of the turnover number and include all steps of the reaction.[3] Intrinsic kinetic isotope values stem from the difference in the bond vibrational environment of an atom in the reactants at ground state to the environment of the atom's transition state.[3] Through the kinetic isotope effect much insight can be gained as to what the transition state looks like of an enzyme-catalyzed reaction and guide the development of transition state analogs.

Computational simulation

Computational approaches have been regarded as a useful tool to elucidate the mechanism of action of enzymes.[4] Molecular mechanics itself can not predict the electron transfer which is the fundamental of organic reaction but the molecular dynamics simulation provide sufficient information considering the flexibility of protein during catalytic reaction. The complementary method would be combined molecular mechanics/ quantum mechanics simulation (QM/MM)methods.[5] With this approach, only the atoms responsible for enzymatic reaction in the catalytic region will be reared with quantum mechanics and the rest of the atoms were treated with molecular mechanics.[6]

Examples of transition state analogue design

After determining the transition state structures using either KIE or computation simulations, the inhibitor can be designed according to the determined transition state structures or intermediates. The following three examples illustrate how the inhibitors mimic the transition state structure by changing functional groups correspond to the geometry and electrostatic distribution of the transition state structures.

Methylthioadenosine nucleosidase inhibitor

Methylthioadenosine nucleosidase are enzymes that catalyse the hydrolytic deadenylation reaction of 5'-methylthioadenosine and S-adenosylhomocysteine. It is also regarded as an important target for antibacterial drug discovery because it is important in the metabolic system of bacteria and only produced by bacteria.[7] Given the different distance between nitrogen atom of adenine and the ribose anomeric carbon (see in the diagram in this section), the transition state structure can be defined by early or late dissociation stage. Based on the finding of different transition state structures, Schramm and coworkers designed two transition state analogues mimicking the early and late dissociative transition state. The early and late transition state analogue shown binding affinity (Kd) of 360 and 140 pM, respectively.[8]

Thermolysin inhibitor

Thermolysin is an enzyme catalyse the hydrolysis of peptide amide bonds with hydrophobic amino acids produced by Bacillus thermoproteolyticus.[9] Therefore, it is also a target to design antibacterial agents. The enzymatic reaction mechanism starts form the small peptide molecule replace the zinc binding water molecule toward Glu143 of thermolysin. The water molecule was then be activated by both zinc ion and Glu143 and attack the carbonyl carbon to form a tetrahedral transition state.(see the figure) Holden and coworkers then mimic that tetrahedral transition state to design a series of phosphonamidate peptide analogues. Among the synthesised analogues, R = L-Leu possesses the most potent inhibitory activity (Ki = 9.1 nM).[10]

Arginase inhibitor

Arginase is a binuclear manganese metallopritein that catalyse the hydrolysis of L-arginine to L-ornithine and urea. It is also regarded as a drug target for the treatment of asthma.[11] The mechanism of hydrolysis of L-arginine was carryout by nucleophilic attack of water molecule forming a tetrahedral intermediate. Studies shown that boronic acid moiety adopts tetrahedral configuration and serve as an inhibitor. In addition, the sulfonamide functional group can also mimic that transition state structure.[12] The evidence of boronic acid mimic as transitions state analogue inhibitor was elucidated by x-ray crystal structure complex with human arginase I.[13]

See also

References

  1. ↑ Silverman, Richard B. (2004). The Organic Chemistry of Drug Design and Drug Action. San Diego, CA: Elsevier Academic Press. ISBN 0-12-643732-7.
  2. ↑ Copeland, R.A.; Davis, J.P.; Cain, G.A.; Pitts, W.J.; Magolda, R.L. (1996). "The Immunosuppressive Metabolite of Leflunomide is a Potent Inhibitor of Human Dihydroorotate Dehydrogenase". Biochemistry 35 (4): 1270. doi:10.1021/bi952168g.
  3. 1 2 Schramm, Vern L> (2011). "Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes". Annu. Rev. Biochem. 80 (1): 703–732. doi:10.1146/annurev-biochem-061809-100742. PMID 21675920.
  4. ↑ Peter, Kollman; Kuhn, B.; Peräkylä, M. (2002). "Computational Studies of Enzyme-Catalyzed Reactions: Where Are We in Predicting Mechanisms and in Understanding the Nature of Enzyme Catalysis?". J. Phys. Chem. B 106 (7): 1537–1542. doi:10.1021/jp012017p.
  5. ↑ Hou, G; Hou, G.; Cui, Q. (2011). "QM/MM Analysis Suggests that Alkaline Phosphatase (AP) and Nucleotide Pyrophosphatase/Phosphodiesterase Slightly Tighten the Transition State for Phosphate Diester Hydrolysis Relative to Solution: Implication for Catalytic Promiscuity in the AP Superfamily". J. Am. Chem. Soc. 134 (1): 229–246. doi:10.1021/ja205226d.
  6. ↑ Schwartz, S; Saen-oon, S.; Quaytman-Machleder, S.; Schramm, V. L.; Schwartz, S. D. (2008). "Atomic Detail of Chemical Transformation at the Transition State of an Enzymatic Reaction". PNAS 105 (43): 16543–16545. Bibcode:2008PNAS..10516543S. doi:10.1073/pnas.0808413105.
  7. ↑ Singh, Vipender; Singh V; Lee JE; Núñez S; Howell PL; Schramm VL. (2005). "Transition state structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Escherichia coli and its similarity to transition state analogues". Biochemistry 44 (35): 11647–11659. doi:10.1021/bi050863a. PMID 16128565.
  8. ↑ Guitierrez, Jemy; Luo, M.; Singh, V.; Li, L.; Brown, R. L.; Norris, G. E. (2007). "Picomolar Inhibitors as Transition-State Probes of 5′-Methylthioadenosine Nucleosidases". ACS Chemical Biology 2 (11): 725–734. doi:10.1021/cb700166z. PMID 18030989.
  9. ↑ S, Endo (1962). "Studies on protease produced by thermophilic bacteria". J. Ferment. Technol. 40: 346–353.
  10. ↑ Holden, Hazel; Tronrud, D. E.; Monzingo, A. F.; Weaver, L. H. (1987). "Slow-and fast-binding inhibitors of thermolysin display different modes of binding: crystallographic analysis of extended phosphoramidate transition-state analogs". Biochemistry 26 (26): 8542–8553. doi:10.1021/bi00400a008.
  11. ↑ Maarsingh, Harm; Johan Zaagsma; Herman Meurs (October 2009). "Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives". Br J Pharmacol. 158 (3): 652–664. doi:10.1111/j.1476-5381.2009.00374.x. PMC 2765587. PMID 19703164.
  12. ↑ E, Cama; Shin H; Christianson DW. (2003). "Design of amino acid sulfonamides as transition-state analogue inhibitors of arginase". J Am Chem Soc. 125 (43): 13052–7. doi:10.1021/ja036365b.
  13. ↑ Shishova, Ekaterina; Luigi Di Costanzo; David E. Cane; David W. Christianson (2009). "Probing the Specificity Determinants of Amino Acid Recognition by Arginase". Biochemistry 48 (1): 121–131. doi:10.1021/bi801911v.
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