Acac Can Tautomerize; Draw The Tautomers. Is This Relevant To The Compound You Synthesized?
J Comput Aided Mol Des. 2009 October; 23(10): 693–704.
Let'south not forget tautomers
Yvonne Connolly Martin
Martin Consulting, 2230 Chestnut St., Waukegan, IL 60087 USA
Received 2009 Jul 28; Accepted 2009 Sep seven.
Abstract
A compound exhibits tautomerism if it can be represented past ii structures that are related by an intramolecular movement of hydrogen from one atom to another. The different tautomers of a molecule usually have unlike molecular fingerprints, hydrophobicities and pKa's besides as dissimilar 3D shape and electrostatic backdrop; additionally, proteins frequently preferentially bind a tautomer that is present in low abundance in water. As a effect, the proper treatment of molecules that can tautomerize, ~25% of a database, is a challenge for every aspect of figurer-aided molecular pattern. Library pattern that focuses on molecular similarity or diversity might inadvertently include similar molecules that happen to be encoded as different tautomers. Concrete property measurements might not institute the properties of individual tautomers with the result that algorithms based on these measurements may exist less accurate for molecules that tin tautomerize—this trouble influences the accuracy of filtering for library blueprint and likewise traditional QSAR. Any second or 3D QSAR analysis must involve the decision of if or how to conform the observed K i or IC50 for the tautomerization equilibria. QSARs and recursive partitioning methods also involve the decision equally to which tautomer(s) to use to summate the molecular descriptors. Docking virtual screening must involve the conclusion equally to which tautomers to include in the docking and how to business relationship for tautomerization in the scoring. All of these decisions are more difficult because at that place is no extensive database of measured tautomeric ratios in both water and non-aqueous solvents and there is no consensus as to the best computational method to calculate tautomeric ratios in different environments.
Keywords: Tautomer, Drug blueprint, Hydrophobicity, Protein recognition
Introduction
Molecules that tin can be as different tautomers are chameleons. Past virtue of a proton hopping from one polar atom to some other and the rearrangement of double bonds or ring opening or endmost, a particular atom changes from a hydrogen-bond donor to an acceptor while another atom in the molecule changes from a hydrogen-bond acceptor to a hydrogen-bond donor. Tautomeric reactions in which a heterocyclic ring is opened and closed also change the shape of the molecule.
Pocket-size changes in molecular structure or solvent environment can dramatically change the ratio of tautomers: Such changes complicate the consignment of a physical property measurement to a specific chemical structure, the identification of the bioactive species from a tautomeric mixture, and the probability that a "minor" species is the one recognized by a macromolecule.
Although there are many reasons for not carefully considering tautomers in computer assisted drug pattern, the time has come up to accept up the challenge. This perspective is non a comprehensive review, but rather a sampling of the experimental information available on tautomers, the implications of these observations, and possible approaches to a more reliable consideration of tautomers in drug pattern. Although others take also highlighted the issue of tautomers [1–vi], the total bear on of tautomerism has not received comprehensive attention from the reckoner-aided drug pattern customs.
Experimental observations of tautomers
Rate of tautomerization
In general, if the tautomerism involves moving a proton from one heteroatom to some other, the reaction is fast, particularly in aqueous solutions [vii]. In these cases, NMR studies see both tautomers [8] and experimental measurements of logP, logD, or pGa contain contributions from all tautomers unless the analytical detection method has been specifically designed to discover but one. On the other paw, tautomerization may exist tedious if information technology involves a ring-concatenation equilibrium or if it involves moving a proton from a heteroatom to carbon atom.
Examples of the human relationship betwixt structure, solvent, and the tautomer ratio
The ratio of tautomers of any compound is highly dependent on the structure of the solute well as the solvent [7, 9]. For example, crystallization weather condition may induce different tautomers of the same molecule or the two forms might co-exist in a single crystal [10–thirteen].
Figure1 shows examples of tautomeric equilibria in water [nine]. Note that the equilibrium between 4-hydroxypyridine and 4-pyridone is affected by the solvent, by intramolecular hydrogen bonding, and by the electronic effects of substituents. In water the thione class of 4-mercaptopyridine predominates, but the equilibrium switches to the thiol form for ii-mercaptothiophene. The absence of numbers for some of the equilibrium constants in Fig.i indicates that although it was possible to establish the predominant tautomer, it was not possible to quantitate the concentration of the minor form.
Construction-activity relationships of tautomeric equilibria in h2o for some uncomplicated substituted heterocycles [9]
Effigy2 shows an example of the change in tautomer ratio every bit a role of solvent and of structure [14]. The replacement of one of a pair of enolizable hydrogens by a methyl group increases the proportion of the NH grade in all solvents and increases the proportion of the OH course in both non-polar solvents. Note that tautomerization would also racemize the chiral carbon of Structure 2.04.
The upshot of changes in structure and solvent on tautomeric equilibria of simple heterocycles [14]
Ring-chain tautomerism is well established in carbohydrates, simply it also occurs in other molecules such as warfarin, Fig.three [xv]. An case of the substituent upshot on this blazon of equilibrium is shown in Fig.4 [16]. Substitution of an ortho hydrogen with a nitro group favors the open course, whereas substitution with an amino or hydroxy group favors the cyclic form. The equilibrium abiding for ring closure follows a Hammett relationship.
The tautomers of warfarin [15]
Structure-action relationships for a chain-ring tautomerization [16]
Clearly if one were comparing the biological properties of the compounds in Figs.1, 2, iii and 4, information technology would be important to be alert to the possibility that tautomerism might complicate the construction-activeness relationships.
Examples of ligand tautomer preferences of macromolecules
Often the resolution of a protein crystal structure cannot conspicuously establish the tautomer of the bound ligand. Withal, at that place are several documented cases where the spring tautomer has been unambiguously established. Figure5 illustrates the contrast betwixt the solution structure of a barbiturate counterpart and that in a 1.8 Å crystal structure as bound to matrix metalloproteinase eight [17]. Others accept shown with SCRF-HF/6-31G** calculations that the tautomer of unsubstituted barbituric acid that corresponds to the bound tautomer is 20.05 kcal/mol less stable in polar medium [18]. Effigyhalf-dozen shows the tautomer of pterin bound to the two.3 Å construction of ricin toxin A-chain. Information technology is three kcal/mol higher in energy (AMSOL in AM1-SM2 Hamiltonians) in solution than the favored tautomer [19].
The recognition of a minor tautomer by matrix metalloproteinase 8 [17]
The recognition of a minor tautomer past the A-chain of ricin toxin [xix]
In some cases more than one tautomer is bound to the protein. For example, Fig.7 shows the two tautomers that are bound with equal occupancy in a ane.53 Å construction of CDK [xx]. This upshot contrasts with crystal structures of similar compounds in KDR [21] and PDGF [22], two other kinases, in which only the 2,4-dihydroindeno tautomer, the left structure, is observed. Macrophage migration inhibitory gene (MIF) catalyzes phenylpyruvate tautomerization, Fig.viii [23]. It catalyzes the reaction in both directions, and hence binds both tautomers, although the enol-keto direction is preferred.
Two tautomers recognized past CDK [xx]
Two tautomers recognized by macrophage inhibitory factor [23]
Enzymes can besides select one species from a ring-chain equilibrium. For example, Fig.ix shows the tautomers of chlorthalidone, a carbonic anhydrase inhibitor. The crystal structure of the carbonic anhydrase II-chlorthalidone complex shows that it is not bound as the amide form, but rather as an unusual lactim tautomer [24].
The recognition of a small-scale tautomer by carbonic anhydrase Ii [24]
Proteins can demark different tautomers of related compounds. For example, glucose is a substrate for xylose isomerase and xylitol is an inhibitor, Fig.10. Interestingly, the 0.95 Å crystal structures evidence that glucose is bound as a ring tautomer, not the chain class as expected from the structure of xylitol [25, 26].
The recognition of sugars past xylose isomerase [26]
A slightly more than complex process is involved with the anti-tuberculosis drug isoniazid. It first forms an adduct with NAD(P); this adduct and then inhibits a long-chain enoyl-acyl carrier protein reductase (InhA) [27]. Figurexi summarizes the structures involved. Measurements on model compounds show that in contrast to the bound construction, in water the ring tautomer is favored by a gene of ii [28, 29].
The inhibition of InhA by an adduct of isoniazid [27]
Complementary hydrogen bonds of bases in DNA lead to the formation of the characteristic double helix of Deoxyribonucleic acid. When the base-pair mimics shown in Fig.12 grade a double helix with complementary Deoxyribonucleic acid, the analogue that positions the tautomerizable grouping in the major groove is in the keto-amino tautomer [30]. Nevertheless, the analogue that binds in the minor groove is in the syn-enol tautomer. The differences in tautomer preferences reflect the differences in the character of the major and modest grooves.
Different tautomers spring to the modest and major grooves of Dna [30]
Frequency of molecules that can tautomerize
A summary of one program'due south enumeration of tautomers [31] of marketed drugs [32] is shown in Fig.13. Of the 1,791 compounds, 1,334 or 74% be every bit simply 1 tautomer—put another style, 26% exist as an average of three tautomers. For this dataset and enumeration program 2,949 tautomers are found; this increases the size of the dataset by 1.64-fold. Using a unlike tautomer generating program, others have establish similar or slightly more than increases in the size of a database [3]. Hence, although consideration of tautomers volition increment the number of structures considered for virtual screening, the increment should be manageable.
The frequency distribution of tautomers of marketed drugs
Calculated properties of tautomers
pOne thousanda Differences between tautomers
Because the tautomers of a molecule have different structures, they differ in their power to gain or lose a proton; their pKa values. In the simple instance of an ionizable molecule that has 2 tautomeric forms, the tautomeric ratio is a function of the pThousanda'south of the tautomers. For example, consider the tautomeric and ionic equilibria of 6-chloro-ii-pyridone in h2o, Fig.14. Algebraically K t =K a OX/K a OH. Hence, one can calculate the value of whatsoever one of these equilibrium constants from values of the other two.
The relationship betwixt the equilibrium constant for tautomerization and the pKa's of the tautomers
The observed pKa of a tautomerizable molecules is a composite of several individual microscopic ionization constants and the tautomeric equilibrium constant(s) [33]. For case, the protonated form tetracycline (Structure10) can be present as any one of ix tautomers, and the neutral class by x [34]. Each of these 19 species could contribute to the observed pGa every bit well equally the biological properties and octanol-water logD of the molecule. Similarly, 8-oxoguanine (Structure11) can exist every bit one or more than of 100 neutral or anionic tautomers. This complicates investigations into its mechanism of mutagenicity [33].
Calculation of the tautomer ratio in solution
Although many workers accept investigated the relative stabilities of tautomers in different liquid phases, because of the difficulty of measuring the equilibrium constants there is no publically available comprehensive database of this data. This lack hinders the development of empirical methods to predict the ratios of tautomers of a molecule. The implications of the lack of experimental data are described in detail in an article on predicting pKa [35], a less complex equilibrium constant.
If the tautomerization involves only the movement of a proton between sites, the tautomer equilibrium abiding tin exist calculated from the pKa of each tautomer. This relationship holds considering deprotonation of the tautomers pb to resonance structures of a common structure. Hammett-type [9] or empirical charge [36] relationships can be used to calculate the pYarda'south of the tautomers and hence the tautomeric ratio. Still, even these calculations have errors in the range of 0.8 log units [35].
More elaborate, but not necessarily more than accurate, calculations involve costless-free energy perturbation [37] or quantum chemical calculations [18, 19, 28, 33, 38–48]. To date at that place appears to be no consensus as to the nigh appropriate method.
Calculated octanol-water logP of tautomers
Usually the tautomers of a molecule take different hydrophobicities. Because small changes in structure or solvent can dramatically change the tautomeric ratio, ignoring the possibility of tautomerism leads to complications in assigning the specific molecular structure of a substance for which octanol-water logP has been measured. Indeed, commonly the tautomer ratio in each phase has not been established. This ambiguity in plow results in inaccuracies of computational models to predict logP. For instance we [49] and others [50] showed empirically that programs that calculate octanol-water logP are less authentic for molecules that can tautomerize.
Calculated logP values are often used to filter compounds for virtual screening, presumably because of its inverse correlation with water solubility [51–53] or permeability [52]. Such relationships have not been investigated to see if they also employ to molecules that can tautomerize.
In improver, calculated logP values might be used to predict brain to blood ratio using the simple equation that includes terms for logP and polar surface area, PSA [54]. Although PSA is quite similar for tautomers, the figures in this report evidence that tautomers of a molecule ordinarily have different hydrophobicities. The question then becomes, which logP value should exist used in the encephalon penetration adding—should nosotros assume that blood is like water and utilize the logP of the dominant form in h2o, or exercise we recognize that tautomerization is fast and employ the logP of the more hydrophobic form to simulate brain tissue?
Figures5, 6, 7 and 8 contain values of octanol-water logP calculated by two popular programs. Note that not simply do the values calculated from the dissimilar programs seldom concur, but often they exercise not even agree as to which tautomer is more hydrophobic. Equally some other instance, Table1 lists the calculated octanol-water logP of the tautomers of sildenafil (Viagra) and phenobarbital. Although the programs advise piddling divergence between Tautomers i and 3 of sildenafil, KowWin predicts that the enol grade, Tautomer 2, is the to the lowest degree hydrophobic, whereas CLOGP and ALOGP suggest that it is the near hydrophobic of the three. As a consequence, CLOGP and ALOGP predict that Tautomer 2 is the predominant form in the water-saturated octanol stage, whereas KowWin predicts that it is the small-scale grade in this stage. Similar contradictions are seen with the calculated logP of phenobarbital tautomers: CLOGP predicts that Tautomer 1, the tautomer most highly populated in water, is also the most hydrophobic tautomer, whereas ALOGP predicts that it is the least hydrophobic tautomer.
Tabular array 1
Calculations of octanol-water log P of different tautomers of viagra and phenobarbital
Cheminformatics issues with tautomers
Identifying if a molecule is in a database
This problem has been discussed by others [3, 55, 56]. Considering the tautomers of a molecule do not have the same molecular structure, they volition usually be encoded differently in the bitmaps or fingerprints that are used to discover if a particular molecule is in a database. An case of different tautomers registered in dissimilar databases is seen with sildenafil: Although Tautomer 3 (Table1) has been reported to exist more than stable than Tautomer 1 and it is the 1 associated with a Chemic Abstracts [57] Number, Tautomer 1 is listed equally the structure in PubChem [58] and ChemSpider [59].
The usual solution to this trouble is to use a special algorithm to generate a unique tautomer, ordinarily ane assumed to predominate in water [three, 55]. Unfortunately, different software vendors apply slightly dissimilar algorithms with the result that the same compound can be represented differently in different databases.
Substructure searching and identification
Substructure search queries that will identify tautomers need to exist constructed with this possibility in mind. For example, if 1 uses Structure 1.03 every bit a search query, if the ring is specified to be effluvious, then molecules that incorporate Substructure 1.04, perhaps as the N-methyl derivative, would non be constitute.
Many cheminformatic investigations involve an assay of the substructures nowadays in the molecules under consideration. For example, QSARs or recursive segmentation may exist based on the relative frequency of certain substructures in active versus inactive compounds: Clearly, such investigations are compromised if they do not include the substructures that are present in any (or most arable?) tautomer of the molecule. The examples in Figs.5, vi, 7, viii, 9, x, xi and 12 testify that i cannot focus exclusively on the "major" tautomer.
Similarity searching
Tabular arrayii shows Tanimoto similarities calculated with ECFP4 fingerprints [31] and the probability, based on the similarity, that the two compounds will take authorisation inside 10-fold of each other [60]. The columns on the left listing the similarities and probabilities betwixt tautomers; the columns to the right listing these values for the most like molecule in this small dataset. Note that in nigh cases the virtually similar molecule is not a tautomer of the query molecule. Only if the query structure is rather circuitous is the tautomer similar. Note the low similarity betwixt Structures 5.01 and 5.02. This effect shows that fifty-fifty uncomplicated similarity searching tin can be misleading if one ignores tautomerization.
Table 2
Tanimoto similarity comparisons of structures (ECFP_4 Fingerprints [31])
| Construction | Tautomer | Nigh similar structure | ||||
|---|---|---|---|---|---|---|
| Tautomer | Similarity | Probability of equal authorisation (%) | Construction | Similarity | Probability of equal potency (%) | |
| 101 | 102 | 0.07 | 0.14 | 103 | 0.43 | xviii.66 |
| 103 | 104 | 0.07 | 0.14 | 105 | 0.43 | 18.66 |
| 105 | 106 | 0.07 | 0.14 | 103 | 0.43 | xviii.66 |
| 107 | 108 | 0.06 | 0.12 | 105 | 0.19 | 0.89 |
| 107 | 109 | 0.06 | 0.12 | 105 | 0.19 | 0.89 |
| 108 | 109 | 0.06 | 0.12 | 106 | 0.23 | 1.62 |
| 110 | 111 | 0.04 | 0.09 | 104 | 0.22 | one.40 |
| 112 | 113 | 0.fifteen | 0.49 | 111 | 0.33 | 6.57 |
| 201 | 202 | 0.30 | 4.42 | 204 | 0.33 | half-dozen.57 |
| 203 | 201 | 0.26 | 2.52 | 206 | 0.33 | half dozen.57 |
| 202 | 203 | 0.22 | 1.40 | 205 | 0.35 | 8.42 |
| 204 | 205 | 0.27 | two.91 | 201 | 0.33 | 6.57 |
| 204 | 206 | 0.25 | two.eighteen | 205a | 0.27 | 2.91 |
| 205 | 206 | 0.25 | 2.18 | 202 | 0.35 | viii.42 |
| 401 | 405 | 0.15 | 0.49 | 404 | 0.43 | 18.66 |
| 402 | 406 | 0.21 | 1.20 | 404 | 0.49 | 26.65 |
| 403 | 407 | 0.23 | 1.62 | 404 | 0.55 | 25.46 |
| 404 | 408 | 0.23 | i.62 | 403 | 0.55 | 32.07 |
| 501 | 502 | 0.42 | 17.23 | 502a | 0.42 | 17.23 |
| 601 | 602 | 0.34 | vii.45 | 602a | 0.34 | seven.45 |
| 701 | 702 | 0.56 | 32.70 | 702a | 0.56 | 32.70 |
| 801 | 802 | 0.38 | 11.81 | 802a | 0.38 | 11.81 |
| 901 | 902 | 0.26 | 2.52 | 902a | 0.26 | 2.52 |
| 901 | 903 | 0.27 | 2.91 | 903a | 0.27 | 2.91 |
| 902 | 803 | 0.47 | 24.20 | 903a | 0.47 | 24.twenty |
aThe most like construction is a tautomer
Because similarity calculations form the footing for clustering and diversity selection, wrong handling of tautomers can result in erratic results.
Tautomer enumeration programs
Cheminformatics software vendors recognize the bug that tautomers cause. As a result, about supply a tautomer enumeration program, by and large only heterocyclic tautomers. To date, in that location has been no comparison of the different programs, probably considering there is no recognized database. The users interested in using a database for virtual screening must then make up one's mind if they will enumerate all possible tautomers or just a few that are likely to exist the most abundant in h2o.
Implications of tautomerization for QSAR
Figuresi, 2 and 3 remind us that within a series the ratio of tautomers in either the water or a non-aqueous phase is non constant. Because QSARs correlate the full concentration of a molecule with some biological issue, tautomerization has the consequence of adding equilibria in addition to those for drug-target and drug-distribution. For instance, correcting the observed concentration to that of "bioactive" tautomer in the aqueous phase does not account for the differential partitioning of tautomers of the various analogues to inert nonaqueous and receptor phases or that the target biomolecule may recognize a modest tautomer.
As noted above, for substructure-based QSARs, the first issue is to make up one's mind which tautomers should be included in the assay. The second outcome is how the algorithm allows the model to ignore some of the tautomers of a molecule.
Tautomerization complicates the calculation of molecular descriptors for traditional second QSAR [61]. For example, it may be ambiguous which calculated logP values to utilize as a molecular descriptor. Hence, the reliability of QSAR analyses that utilize hydrophobicity as a descriptor may suffer. In addition, considering tautomers of a molecule have different pKa's, assigning a concrete property to a specific molecular construction is especially challenging if the molecule can also ionize at pHs of involvement [62]. On the other mitt for 3D-QSARs, one must decide which tautomer as well as which conformer to use for the analysis.
Implications of tautomerization for docking molecules
High throughput docking programs are generally imprecise plenty that one can attempt to dock all reasonable tautomers of a molecule. If the objective of the study is to identify compounds for experimental testing, if any tautomer of a molecule has a high score, validation is provided past experimental testing.
On the other manus, if the objective of the docking is to advise the construction of the poly peptide-ligand complex, the preliminary docked structures would so exist refined to optimize the fit and provide a prediction of affinity. This optimization would involve exploring the conformation of the ligand and the poly peptide active site as well every bit the protonation and tautomeric land of both.
One strategy is to optimize and calculate the free energy of every possible tautomeric and protonation land of the system, both in water and in the active site. This can be done with molecular mechanics force-fields [vi, 19, 63, 64], with quantum mechanics [25, 29, 64–66], or a combination of the two [67]. At the current fourth dimension, no method is specially accurate—errors of 0.7–1.0 log units for each of the components are not uncommon [35, 67–69]. A quantum mechanical or QM/MM structure optimization would reveal the bound tautomer of both the ligand and the protein [67, 70]. For such calculations 1 would have to determine the level of theory necessary and whether the whole complex will be treated quantum mechanically or, if not, how the purlieus between the breakthrough and molecular mechanics will be handled. Because a thermodynamic bicycle is involved, the apply of any method requires that it tin reliably predict the ratio of tautomers in aqueous systems.
Directions for the future
The need for more experimental information
This review emphasizes the need for more experimental information on the tautomeric ratio of various molecules in water and diverse solvents. Such observations would form the ground for methods to predict the tautomeric ratio and a exam bed to compare the accurateness of the various empirical and quantum chemical methods. Unfortunately, these measurements are difficult to pattern and often require synthesis of model compounds in hopes that they accurately mimic the properties of the corresponding tautomer.
Conscientious measurement of the touch on of tautomerization on pThoua and water solubility would provide information that would improve the predictions of these properties.
The demand for cheminformatic databases that can maintain information about tautomers
Once a body of information is available, information technology might be discovered that enhancements must be made to the current architecture for storing chemical structures and data [56]. For example, consider the problem of a database that would store all of the tautomers of Structures10 or 11. Such a database would need to store non only the canonical tautomer but also structures and bachelor backdrop of each private tautomer, the measured or calculated equilibrium constants between the tautomers, and the backdrop of the compound itself.
The need for reckoner programs that predict ring-chain tautomerization
Rules for band germination in organic synthesis have been formulated past Baldwin [71]. These would provide a starting point for a program that would enumerate ring-chain tautomers, a capability absent from the current tautomer generation programs.
The demand for validation of the diverse computational methods
Although the various methods to explore the structure and energetics of enzyme-ligand complexes are interesting, for such methods to exist useful they must be validated. For example is the continuum solvent supposition sufficient, or is information technology important to include explicit water molecules in the adding? Earlier QM/MM calculations can exist used in routine investigations of poly peptide-ligand complexes, they will need to run faster and with less homo interaction. A point to exist examined would be whether a semi-empirical method [72, 73] might exist sufficient for the quantum mechanical portion of the calculation and, indeed, whether the whole system can be accurately calculated with semi-empirical methods.
Summary
Tautomerization equilibria present a standing challenge to computer-aided molecular design, affecting everything from library design to SAR to docking and scoring protein-ligand interactions. The absenteeism of experimental data and validated computational methods brand tautomerization easy to ignore but overwhelming to consider.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776169/
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