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Stacking Interactions between 9‑Methyladenine and Heterocycles Commonly Found in Pharmaceuticals Yi An,† Analise C. Doney,† Rodrigo B. Andrade,‡ and Steven E. Wheeler*,† †

Department of Chemistry, Texas A&M University, College Station, Texas 77842, United States Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States

‡

S Supporting Information *

ABSTRACT: Complexes of 9-methyladenine with 46 heterocycles commonly found in drugs were located using dispersion-corrected density functional theory, providing a representative set of 408 unique stacked dimers. The predicted binding enthalpies for each heterocycle span a broad range, highlighting the strong dependence of heterocycle stacking interactions on the relative orientation of the interacting rings. Overall, the presence of NH and carbonyl groups lead to the strongest stacking interactions with 9-methyadenine, and the strength of π-stacking interactions is sensitive to the distribution of heteroatoms within the ring as well as the specific tautomer considered. Although molecular dipole moments provide a sound predictor of the strengths and orientations of the 28 monocyclic heterocycles considered, dipole moments for the larger fused heterocycles show very little correlation with the predicted binding enthalpies. benzene. On the other hand, Gellman and co-workers17,46 previously emphasized the importance of local dipole moments47−51 in understanding heterocycle stacking as well as the unreliability of analyzing stacking interactions in terms of molecular dipoles.52 This echoes our recent work on substituent effects in π-stacking interactions,53−60 which can be understood in terms of the electrostatic interaction of the local dipole moment associated with the substituent and the other ring,58 as well as the seminal model of heterocycle stacking interactions from Hunter and Sanders.61 Despite progress in understanding π-stacking interactions involving heterocyclic rings,34−45 the rational design of heterocycle-containing molecules that maximize π-stacking interactions with a given aromatic group remains a challenge. A number of studies have focused on identifying common heterocyclic fragments within drug-like and bioactive molecules.13,62,63 For example, Broughton and Watson62 identified heterocyclic motifs found in drugs that have reached phase II clinical trials or later stages, reporting the 30 most frequently identified heterocycles with favorable absorption, distribution, metabolic, excretory, and toxicity (ADMET) characteristics. Ertl and co-workers63 analyzed an expansive virtual library of heteroaromatic scaffolds and investigated the structural, bioactivity, and electronic properties of these molecules. Six heterocyclic fragments with fused rings were found to be wellrepresented in bioactive molecules. Finally, Vitaku and coworkers13 analyzed nitrogen heterocycles by exploring their structural diversity and substitution patterns, identifying 25 of

I. INTRODUCTION Stacking interactions are central to many areas of chemistry, including the binding of ligands to proteins and nucleic acids,1−3 and harnessing such interactions lies at the heart of drug design.4,5 In this context, understanding π-stacking interactions involving heterocycles is of paramount importance because heterocyclic fragments abound in drugs and bioactive natural products.6−13 Model π-stacking interactions involving heterocycles have been studied both experimentally14−22 and theoretically,23,24 with the primary aim of unraveling the many factors that control their strength and preferred orientation. For instance, there have been numerous computational studies25−33 of non-covalent interactions involving pyridine as a model Nheterocycle, building on the seminal work on the benzene− pyridine and pyridine−pyridine dimers by Hohenstein and Sherrill.34 Stacking interactions of other six-membered Nheterocycles (pyrimidine, triazine, tetrazine, etc.)35−38 as well as thiophene and benzothiophene, pyrrole, imidazole, indole, and larger bioactive molecules39−45 have also been investigated computationally. Recently, Huber and co-workers45 presented a comprehensive computational study of stacked dimers of benzene with five- and six-membered aromatic heterocycles found in small drug-like molecules. Ultimately, they concluded that even though dispersion interactions are a significant driver of these stacking interactions, electrostatic effects play a key role in determining the preferred orientation of a given stacked dimer. Moreover, in accord with general guidelines for stacking interactions in drug design,4 Huber and co-workers reported45 a correlation between the molecular dipole moments of these small heterocycles and their predicted stacking interactions with © XXXX American Chemical Society

Received: October 27, 2015

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DOI: 10.1021/acs.jcim.5b00651 J. Chem. Inf. Model. XXXX, XXX, XXX−XXX

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Journal of Chemical Information and Modeling

drive to provide a more comprehensive understanding of πstacking interactions involving heterocycles, we present a computational study of model stacking interactions between 9-methyladenine and a set of heterocycles commonly found in pharmaceuticals (see Charts 1 and 2). The primary aim is to

the most commonly utilized heterocycles among U.S. Food and Drug Administration (FDA)-approved pharmaceuticals. Interactions of heterocycles with aromatic amino acid side chains and nucleic acids abound in drug binding sites.64−69 For instance, Pyrkov et al.70 analyzed the role of π-stacking interactions in proteins with adenine- and guanine-containing fragments bound. Futhermore, the Andrade group has a longstanding interest in ketolide antibiotics such as telithromycin (TEL) (see Figure 1a),71−75 which feature an extended

Chart 1. Structures of Five- and Six-Membered Heterocycles and 9-Methyladenine; For Tautomeric Series (10 and 11, 12 and 13, 14 and 15), the B97D/def2-TZVPP-Predicted Tautomerization Enthalpies Are Provided in Parentheses

Figure 1. (a, b) Structures of the ketolides (a) telithromycin (TEL) and (b) solithromycin (CEM-101). (c) Structure of solithromycin in the binding site of E. coli 70S ribosome (PDB ID 4WWW).

heterocyclic alkyl−aryl side chain attached to the macrocycle76,77 and exhibit tighter binding to the ribosome compared with previous classes of macrolides.78 Despite the excellent activity of TEL against many macrolide-resistant bacteria,79 the FDA narrowed its approved clinical use because of adverse effects and safety concerns.80 The search continues for newer ketolides that both address bacterial resistance and minimize consumer risks. Accordingly, Andrade and co-workers synthesized and evaluated 4-desmethyl-TEL, 4,8-didesmethyl-TEL, 4,10-didesmethyl-TEL, and 4,8,10-tridesmethyl-TEL to explore structure−activity relationships of methyl groups on the macrolactone ring implicated in known resistance mechanisms.71−75,81 Changing the alkyl−aryl side chain may provide an alternative way to tune the activity of telithromycin. For example, the structure of solithromycin, which is now undergoing phase III clinical development for the treatment of community-acquired bacterial pneumonia (CABP), urethritis, and other infections,82 differs from that of telithromycin in that the alkyl−aryl side chain contains triazole and aniline groups (see Figure 1b). This side chain engages in π-stacking interactions with the uracil−adenine pair (A752 and U2609) in the binding site of the Escherichia coli ribosome (see Figure 1c).82 More precisely, the NH2 of the aniline hydrogen-bonds with the ribose backbone of A752, the triazole stacks with U2609, and the aniline fragment stacks with A752. However, because of the currently limited understanding of π-stacking interactions involving heterocycles, it is not apparent what heterocycles can replace this aniline to enhance the stacking interactions with the adenine. Motivated by a desire to explore derivatives of solithromycin that maximize π-stacking interactions with A752 as well as a

delineate the structural features that lead to the most favorable stacking interactions with adenosine in order to guide the rational design of pharmaceuticals expected to engage in such interactions upon binding. Although the stacked dimers considered are not guaranteed to contain the globalChart 2. Structures of Fused Heterocycles

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Journal of Chemical Information and Modeling minimum-energy stacked complex, they provide a representative set of stacked configurations for these heterocycles.

II. THEORETICAL METHODS A representative collection of 46 heterocycles (see Charts 1 and 2) were selected to assess their propensities to form stacked dimers with 9-methyladenine as a model of adenosine. This set of heterocycles includes the conjugated systems identified by Vitaku and co-workers13 and Broughton and Watson62 from their analyses of the structures of popular pharmaceuticals. Also included are various analogues of these heterocycles, including structural isomers, tautomers, isoelectronic congeners, etc. Although some of these other heterocycles are not realistic as drug fragments because of bioavailability or stability issues, whereas others are not the most favorable tautomer, they all serve to provide a more comprehensive view of the features of heterocycles that impact their π-stacking interactions with 9methyladenine. This set of heterocycles has been divided into two main categories: five- and six-membered monocyclic species (Chart 1) and heterocycles with two or three fused rings (Chart 2). The binding enthalpies (0 K) of each of these 46 heterocycles with 9-methyladenine were computed in the gas phase at the B97D/def2-TZVPP level of theory83−86 at a large number of representative stacked geometries. B97D, when paired with a triple-ζ basis set, has been shown to provide accurate non-covalent binding enthalpies for a wide range of model non-covalent complexes, including π-stacked dimers.84,87 Although these gas-phase computations neglect differences in the desolvation costs of the different heterocycles, these results should lay the groundwork for more detailed studies of the binding of these fragments in more realistic environments. To locate representative low-lying stacked dimer configurations, we systematically sampled different relative positions and orientations of each heterocycle with 9-methyladenine (see Figure 2). In particular, 108 initial stacked geometries (fewer in the case of symmetric heterocycles) were constructed for each heterocycle by considering nine initial positions of the heterocycle above the face of 9-methyladenine with the heterocycle located 3.6 Å above and parallel to the molecular plane of 9-methyladenine. At each of these nine positions, we considered 12 relative orientations (six equally spaced orientations for each face of the heterocycle; see Figure 2b). These initial structures were then optimized to the nearest energy minimum, as confirmed by the absence of imaginary harmonic vibrational frequencies. Unique optimized complexes were identified as those for which the root-mean-square deviation (RMSD) exceeded 0.4 Å with all of the other structures. Geometry optimizations of many of these structures resulted in nonstacked configurations (e.g., edge-toedge hydrogen-bonding arrangements, etc.), which were eliminated. Complexes were considered to be stacked when the closest-approaching rings from the two monomers satisfied the criteria shown in Figure 2c.88 In total, 408 unique stacked complexes were identified, providing a representative sample of favorable stacking modes for each heterocycle. Stacking enthalpies were evaluated at the B97D/def2-TZVPP level of theory as the difference between the 0 K enthalpies of the optimized complexes and the optimized isolated monomers. All of the computations were carried out using Gaussian 0989 and utilized density-fitting techniques.

Figure 2. (a) Schematic representation of the nine starting positions of the centroid of each heterocycle above the face of 9-methyladenine. (b) For each of the nine positions in (a), we considered 12 (fewer in the case of symmetric heterocycles) relative orientations of each heterocycle (isoxazole (4) is used here as an example), giving a total of 108 initial dimer geometries for each heterocycle (fewer in the case of symmetric heterocycles). Nonpolar hydrogens have been omitted for clarity. (c) Criteria used to distinguish stacked from nonstacked configurations.

III. RESULTS AND DISCUSSION For each heterocycle, numerous stacked energy minima were located, corresponding to different relative orientations and positions of the heterocycle above the face of 9-methyladenine. The overall distributions of binding enthalpies for each heterocycle are plotted in Figures 3 and 4. All of the complexes considered are in arrangements in which the molecular planes are roughly parallel and with a significant degree of overlap; C


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Figure 3. Distributions of predicted stacking enthalpies (0 K, in kcal mol−1) for stacked dimers of 9-methyladenine with heterocycles 1−28. The number of unique minima for each heterocycle is indicated in parentheses.

Figure 5. Most favorable stacked dimers of 9-methyladenine and heterocycles 1−28. B97D/def2-TZVPP-predicted binding enthalpies (in kcal mol−1) and interplanar angles (β, in deg) are provided in parentheses. Other parameters characterizing the stacking interactions are provided in Table S1 in the Supporting Information. Nonpolar hydrogens have been omitted for clarity.

In general, the larger rings (29−46) exhibit far greater numbers of unique stacked energy minima than the smaller rings (1−28). In particular, whereas the small rings average 5.0 unique complexes, the larger rings average 14.8 unique configurations. Similarly, many of the smaller rings exhibit only one or two unique stacked orientations, while there are at least six unique complexes for all of the larger heterocycles; many of the larger heterocycles exhibit 10 or more distinct stacked configurations. Finally, even though the binding enthalpies of the larger rings are typically more favorable, many of the smaller rings show substantial binding enthalpies. For the five-membered rings (1−16), there is a considerable spread in the binding enthalpies among the most favorable stacked complexes for each heterocycle, ranging from −5.1 kcal mol−1 for 2 to −11.5 kcal mol−1 for 28. The results for the triazoles (10−13) and tetrazoles (14 and 15) are particularly notable, revealing several trends that are seen again for the other classes of heterocycles. For example, 4H-1,2,4-triazole (11), with a predicted binding enthalpy of −9.5 kcal mol−1, shows the most favorable binding enthalpy among all of the five-membered rings. For its lower-lying tautomer, 1H-1,2,4triazole (10), the predicted binding enthalpy is 1.6 kcal mol−1 less favorable. This can be contrasted with the stacking enthalpies for tautomeric pairs 12 and 13 as well as 14 and 15. In both cases, the less stable conformer engages in more

Figure 4. Distributions of predicted stacking enthalpies (0 K, in kcal mol−1) for stacked dimers of 9-methyladenine with heterocycles 29− 46. The number of unique minima for each heterocycle is indicated in parentheses.

however, many of the heterocycles engage in additional interactions with 9-methyladenine in these stacked orientations. These include CH/π and NH/π interactions, in which the edge of one ring is tilted slightly toward the face of the other ring. Moreover, the strengths of the π-stacking interactions are modulated by direct interactions53−60 between functional groups on the heterocycle and 9-methyladenine. These direct interactions appear to be pivotal in determining the preferred orientation of the stacked rings and can be understood to arise from the heterogeneous distribution of charge within these heterocycles.17,46 Below we will focus primarily on the lowestenthalpy stacked complex located for each heterocycle; the structures of these complexes are depicted in Figures 5 and 6. D


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engage in stronger stacking interactions than their sulfur analogues, thiazole (7) and isothiazole (6), which lack NH groups. Comparison of the various oxygen- and sulfurcontaining rings (2 vs 3, 4 vs 6, and 5 vs 7) shows that there is no substantial difference in the predicted stacking enthalpies despite the greater polarizability of sulfur compared with oxygen. The six-membered rings (17−28) exhibit a narrower range of predicted binding enthalpies than the five-membered rings. This group is primarily composed of benzene (17) and the isoelectronic azines that result from the incorporation of between one and four nitrogens into the ring. These nitrogencontaining heterocycles all exhibit more favorable π-stacking interactions with 9-methyladenine than benzene (−5.7 kcal mol−1). For example, the single nitrogen atom in pyridine results in a 1.6 kcal mol−1 enhancement of the binding enthalpy compared with benzene. However, the incorporation of a second nitrogen does not always lead to further enhancement of the interaction. For example, 1,4-pyrazine (19) and 1,3pyrazine (20) engage in π-stacking interactions with 9methyladenine that are slightly weaker than that of pyridine, whereas 1,2-pyrazine (21) is predicted to provide stronger stacking compared with pyridine. The triazines (22−24) show similar trends, with 1,3,5-triazine (22) leading to reduced stacking compared with pyridine but the less-symmetric triazines (23 and 24) leading to more favorable stacking interactions than predicted for pyridine. The most favorable interaction for the triazines is predicted for 1,2,3-triazine (24). All three of the tetrazines (25−27) provide more favorable stacking interactions than pyridine. As seen with 11, many of the six-membered N-heterocycles display interactions between a ring nitrogen and the methyl group of 9-methyladenine, again suggesting that this is an important stabilizing interaction. Finally, we note that pyrimidine (28) engages in much more favorable stacking interactions with 9-methyladenine (−11.5 kcal mol−1) than any of the other monocyclic heterocycles. Turning next to the fused heterocycles (29−46), we see that, on average, these engage in much stronger π-stacking interactions with 9-methyladenine, with predicted binding enthalpies ranging from −8.5 to −12.5 kcal mol−1. As with the small rings, the predicted stacking enthalpies are sensitive to the distribution of heteroatoms within each ring. For instance, indole (29) and isoindole (30) exhibit stronger stacking interactions than indolizine (31). In the former case, a strained NH···N hydrogen-bonding interaction causes indole to deviate significantly from a parallel stacked arrangement. Isoindole, on the other hand, exhibits a nearly parallel configuration that is further enhanced by the unconventional NH···N1 interaction seen for many of the monocyclic N-heterocycles. Similarly, 1,8naphthyridine (33) exhibits stronger stacking interactions than quinazoline (34); there are two N···H3C interactions in the former case but only one in the latter case. The minimumenthalpy complexes of 38 and 39 also exhibit such interactions. Indeed, many of these larger heterocycles exhibit the same local, direct interactions as their smaller analogues. For example, the preferred stacking pose of 32 is similar to that of 18. However, the preferred orientation of the component rings is not always predictive of the preferred orientation of the fused heterocycles. For instance, the pyrimidine ring in quinazoline (34) is shifted significantly compared with pyrimidine itself (20). With regard to broader trends, all of the heterocycles show a marked sensitivity to the orientation relative to 9-methyl-

Figure 6. Most favorable stacked dimers of 9-methyladenine and heterocycles 29−46. B97D/def2-TZVPP-predicted binding enthalpies (in kcal mol−1) and interplanar angles (β, in deg) are provided in parentheses. Other parameters characterizing the stacking interactions are provided in Table S1. Nonpolar hydrogens have been omitted for clarity.

favorable stacking interactions with 9-methyladenine. For the latter pair of heterocycles, the difference in stacking enthalpies (2.0 kcal mol−1) is commensurate with the 2.0 kcal mol−1 tautomerizatoin enthalpy, indicating that the tautomer present in a given binding site could differ from that favored for the isolated heterocycle. In other words, the enhanced stacking that is possible for 14 compared with 15 can compensate for the enthalpy required to form this less stable tautomer. In the case of 11, the stacking interaction appears to be enhanced by favorable direct interactions between the NH group of the triazole and N1 of 9-methyladenine as well as between a ring nitrogen of 11 and the methyl group of 9methyladenine (Figure 5). Notably, the former interaction is not a conventional NH-donated hydrogen bond, since the N··· H−N angle is far from linear ( 3 ≈ 2. In the case of 1, the enhanced π-stacking interaction appears to stem from the ability of pyrrole to engage in a nonconventional NH···N interaction with N7 of adenine. This NH···N7 interaction also appears in the lowest-lying stacked dimers for pyrazole (9); there is a similar NH···N1 interaction in the lowest-lying stacked dimer of imidazole, 8. Both of these heterocycles E


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heterocycles (29−46), there is a much weaker correlation with the molecular dipole moment (r2 = 0.29; see Figure 7). It is not suprising that molecular dipole−dipole interactions fail to predict the strength of π-stacking interactions for larger systems because the multipole expansion, of which the dipole−dipole interaction is the leading term, becomes less reliable as the size of the interacting systems grows with respect to the intermolecular distance. Thus, although the leading dipole− dipole term provides a reliable predictor of stacking interactions for small heterocycles, these interactions are more readily understood in terms of direct interactions of the functional groups on the two stacked systems (or, similarly, in terms of local dipole moments as championed by Gellman and coworkers17,46).

adenine, as indicated by the wide spread in the predicted binding enthalpies shown in Figures 3 and 4. This is perhaps unsurprising given the established importance of electrostatic effects in heterocycle stacking and the heterogeneous distribution of charge around these rings.39−45 However, this sensitivity has important implications for understanding stacking interactions in drug binding sites. In particular, even though a given heterocycle might engage in strong π-stacking interactions with 9-methyladenine, this might require a relative orientation that is not compatible with a given binding site. For instance, 1,2,3-triazine (24) is capable of engaging in strong πstacking interactions with 9-methyladenine, with a predicted binding enthalpy of −8.8 kcal mol−1. However, this is only true for the orientation pictured in Figure 5, in which the nitrogens of the triazine can interact with the methyl group of the 9methyladenine. In the other stacked orientation identified, the predicted binding enthalpy is reduced to −6.3 kcal mol−1. Similar observations hold for other heterocycles, including 9, 12, 13, 18, 25, 28, and 29, for which the stacking enthalpy of the lowest-lying complex exceeds that of the next low-lying complex by more than 1 kcal mol−1. The above discussion has been cast primarily in terms of direct interactions between functional groups on the heterocycle and those of adenine (e.g., nonconventional NH···N and N···H3C interactions). However, in light of the recent work by Huber and co-workers,45 we also explored the ability of molecular dipole moments to predict the binding enthalpies of these stacked complexes with 9-methyladenine. Overall, the molecular dipole moments of the heterocycles are poorly correlated with the total binding enthalpies for the minimumenthalpy stacked complexes of the heterocycles (see Figure 7).

IV. SUMMARY AND CONCLUDING REMARKS Representative π-stacking interactions of 9-methyladenine with 46 common heterocyclic drug fragments were predicted at the B97D/def2-TZVPP level of theory. Overall, 408 unique stacked complexes were identified, exhibiting a broad range of predicted binding enthalpies. Many of these interactions are highly favorable, and variation of the heterocycles within DNA- and RNA-binding pharmaceuticals should provide a powerful means of tuning their binding affinities by modulating the stacking interactions of these groups with adenosine (e.g., see Figure 1c). The broad range of predicted binding enthalpies for each of the heterocycles highlights the impact of the relative orientation on the stacking of heterocycles, with important implications for drug design. Overall, larger heterocycles engage in stronger π-stacking interactions than their smaller analogues. However, many of the features that impact the preferred orientation of the smaller rings are mirrored in the larger systems, leading to the identification of several structural features that lead to strong stacking interactions of heterocycles with 9-methyladenine. Most notably, heterocycles with NH groups exhibit strong πstacking interactions with 9-methyladenine, presumably because of the favorable interaction between this NH group and the nitrogen atoms within the adenine ring. Similarly, nonconventional N···H3C interactions occur in the lowestlying complex for many of the heterocycles, suggesting that this is another factor that enhances the π-stacking interactions of Nheterocycles with 9-methyladenine. For all of the heterocycles considered, the distribution of heteroatoms within each ring and the particular tautomer considered strongly impact the predicted stacking interactions. In the case of tetrazole, the difference in the stacking enthalpies for the different tautomers is of comparable size to the tautomerization energy, suggesting that the tautomer present in the bound state could differ from that favored for the isolated heterocycle. Finally, we found that molecular dipole moments can provide a qualitative predictor of the strengths of stacking interactions of small heterocycles (five- and six-membered rings) with 9-methyladenine, but they are not well correlated with the predicted binding enthalpies of the larger fused heterocycles. Instead, both the preferred orientations and stacking interactions can be more readily explained in terms of local, direct interactions between functional groups on the two interacting systems.

Figure 7. Predicted binding enthalpies for the lowest-enthalpy stacked dimers of 9-methyladenine with heterocycles 1−46 vs the molecular dipole moments of the heterocycles. The slope and r2 values apply to the best-fit lines for the small rings (1−28) and large rings (29−46) separately.

However, there is a correlation for the monocyclic heterocycles (r2 = 0.73), suggesting that in these cases molecular dipole moments provide at least a qualitative predictor of π-stacking strengths with 9-methyladenine. This echoes the recent work of Huber and co-workers45 regarding stacking interactions of small heterocycles with benzene. Moreover, for nearly all of these small heterocycles, the most favorable stacked configuration corresponds to an orientation that features oppositely oriented molecular dipoles (for examples, see Figure S1 in the Supporting Information). However, in the case of the fused F


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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jcim.5b00651. Additional computational data and figures, absolute enthalpies, and optimized Cartesian coordinates (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by The Welch Foundation (Grant A1775) and the National Science Foundation (Grant CHE1254897). We also acknowledge the Texas A&M High Performance Research Computing Facility for computational resources.

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