Molecular Modeling of the Interactions between Carborane

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Molecular Modeling of the Interactions Between CarboraneContaining Analogs of Indomethacin and Cyclooxygenase-2 Menyhárt-Botond Sárosi, Wilma Neumann, Terry P. Lybrand, and Evamarie Hey-Hawkins J. Chem. Inf. Model., Just Accepted Manuscript • DOI: 10.1021/acs.jcim.7b00113 • Publication Date (Web): 20 Jun 2017 Downloaded from http://pubs.acs.org on June 23, 2017

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Journal of Chemical Information and Modeling

Molecular Modeling of the Interactions between Carborane-Containing Analogs of Indomethacin and Cyclooxygenase-2 Menyhárt-Botond Sárosi,a,* Wilma Neumann,a,† Terry P. Lybrand,b Evamarie Hey-Hawkinsa,* a

Leipzig University, Faculty of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Johannisallee 29, D-04103 Leipzig, Germany b

Departments of Chemistry and Pharmacology, Center for Structural Biology, Vanderbilt University, Nashville, TN 37232-8725, United States

KEYWORDS: carborane-containing pharmacophores, indomethacin derivatives, cyclooxygenase, docking simulations, quantum mechanics, molecular mechanics.

ABSTRACT: Molecular modeling studies were performed in order to gain insight into the binding mode and interaction of carborane-containing derivatives of indomethacin methyl ester with the cyclooxygenase-2 (COX-2) isoform, and to assess the predictive capability of the computational tools available for studying carboranes, a unique class of pharmacophores. Docking simulations were able to identify the correct binding mode and reproduced the experimental binding affinity trends with encouraging quality. Nevertheless, the docking results needed to be verified through extensive and resource-intensive quantum chemical calculations, and the interpretation of the 1

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theoretical results would not have been straightforward without the supporting experimental data. The inclusion of full receptor and ligand flexibility into the molecular modeling of carboranecontaining drug molecules may yield more definitive results, but is currently hindered by the lack of appropriate carborane force field parameters.

INTRODUCTION The homodimeric integral membrane protein cyclooxygenase (COX) plays a key role in the biosynthesis of prostanoids and is present in two isoforms with similar structure and high sequence identity.1 An important difference between the two COX isoforms is that COX-1 is constitutively expressed and primarily involved in normal physiological functions whereas COX-2 is induced mainly by pathological processes such as inflammation and tumorigenesis. The known side effects of nonselective COX inhibitors (nonsteroidal anti-inflammatory drugs, such as indomethacin) prompted the development of COX-2-selective inhibitors. Furthermore, COX-2 selective inhibitors are promising antitumor drugs, as COX-2 is overexpressed in various tumor cells.1 The selectivity of existing COX inhibitors can be shifted towards COX-2 by exploiting the differences in size and flexibility of the binding sites of the two COX isoforms.2,3 Indomethacin is a potent, relatively non-selective COX inhibitor.4,5 Conversion of the aryl acetic acid into the neutral methyl ester (1, Figure 1) results in good COX-2 selectivity.3,4 The binding mode of indomethacin has been characterized by means of protein crystallography.6 To the best of our knowledge, no crystal structure of COX-2 complexed with 1 has been published so far. Nevertheless, extensive structure-activity studies have suggested that the binding mode of COX-2selective ester and amide derivatives of indomethacin is similar to that of indomethacin.3,7,8

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Moreover, certain chemical modifications of the 4-chlorobenzoyl group in indomethacin can confer COX-2 selectivity.3,4,9 Recently, carborane clusters and their derivatives have become the focus of intense research in medicinal chemistry and drug design. These icosahedral carbon and boron clusters have been increasingly employed as pharmacophores by incorporating them into drug molecules as phenyl mimetics.10,11 The 1,2-, 1,7-, and 1,12-dicarba-closo-dodecaborane(12) isomers (termed ortho, meta, and para isomer, respectively) and the decapped anionic nido-dicarbaundecaborates serve as threedimensional analogs of aromatic hydrocarbons. Inspired by derivatizations resulting in COX-2 selectivity,3,4 we recently reported carborane analogs of indomethacin.12 The replacement of the 4-chlorophenyl ring in 1 with an ortho-carborane cluster generates a highly potent and selective COX-2 inhibitor (3o in Figure 1).13 In contrast, incorporation of the meta- or para-carborane isomers into the inhibitor structure (3m and 3p in Figure 1, respectively) results in loss of both COX-1 and COX-2 inhibitory activity.13 The reason for this isomer-dependent activity profile is unknown and warrants further investigation. The amide bond in 3o is prone to hydrolysis, and the carbonyl group adjacent to the orthocarborane also increases the lability of the cluster towards deboronation.14 Directed decapping of the closo cluster to an anionic 7,8-nido-dicarbaborate (2, Figure 1) not only preserves the high COX-2selective inhibitory activity, but also improves the solubility and stability of the carboranecontaining inhibitor.12 The crystal structure of COX-2 complexed with 2 at 2.29 Å resolution revealed a binding mode strikingly different from that of indomethacin. Compared to indomethacin, compound 2 is flipped along the longitudinal axis of the indole moiety in the COX-2 channel and the nido cluster protrudes into a hydrophobic pocket that is specifically opened up in the COX-2:2 complex. The exact position of the carbon and boron atoms within the cluster could not be 3



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determined, so it was not possible to assign the stereochemistry definitively. Therefore, both enantiomers of 2 were modeled into the crystal structure. However, docking calculations suggested a higher binding probability for the S enantiomer and helped rationalize the role of the planar chirality of the nido-dicarbaborate in influencing binding affinities.12 These docking studies also hint at differences in the binding between the isomers of the closo cluster (3o,m,p) at COX-2, which may contribute to the differences observed for the inhibitory activities of these derivatives

Figure 1. Indomethacin, the methyl ester 1 and carborane-containing derivatives.

Carboranes are known to interact with proteins through B–H···H–X (X = N, C and S) dihydrogen bonds, B–H···Na+ bridging interactions, and B2H···π and C–H···π hydrogen bonds.15-21 The acidic 4


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C–H moiety also forms C–H···X hydrogen bonds,

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and might also interact with water through

weak C–H···OH2 interactions.22 The B–H···H–X (X = N, C and S) dihydrogen bonds observed for boranes exhibit short hydrogen–hydrogen contacts in the range of 1.7–2.2 Å.23 It has been suggested that the mildly acidic carborane C–H protons might play an important role in influencing the biological activity of carborane-containing derivatives. In the case of the carborane derivatives of the local anesthetic lidocaine, a higher exposure of the carborane C–H protons to the surrounding protein residues correlated with the loss of analgesic activity.24 Carborane-containing compounds are becoming more frequently the subject of in silico drug design and molecular modeling studies. Tjarks and co-workers tested the capability of several docking software packages for predicting the binding mode of closo- and nido-carboranyl-based drug molecules.25 AutoDock proved to be one of the best performing programs and also allowed for straightforward implementation of boron parameters. However, the authors pointed out that further refinement of carborane cluster parameters is needed for future docking calculations. Allinger and co-workers developed molecular mechanics (MM) force field parameters for modeling the bonding interactions of 12-vertex boranes and carboranes and successfully reproduced the experimental structures of substituted carboranes.26 Gamba and Powell developed an atom–atom Lennard-Jones (LJ) model for the intermolecular potential of carborane molecules for classical molecular dynamics (MD) simulation of o-, m-, and p-carborane crystals.27 Wimperis and co-workers combined the LJ parameters of Gamba and Powell with the bonding interaction parameters of Allinger and coworkers to perform MD simulations that were in qualitative agreement with carborane solid-state magic angle spinning NMR results.28 Roccatano and co-workers developed parameters for both LJ and bonding interactions in order to study the structure and dynamics of dodecaborate cluster (B12H122−) derivatives in water.29 However, none of the above-mentioned studies investigated the 5



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interaction of carborane-containing compounds with biomolecules and the parameters used in these previous studies are not directly transferable to the carborane-containing derivatives of indomethacin. Previous studies have demonstrated the reliability of dispersion-corrected density functional theory (DFT-D) for describing protein–ligand interactions,30,31 and a combined quantum mechanics and molecular mechanics (QM/MM) protocol using DFT-D as the QM method has been successfully applied to study carborane−protein interactions.32 In this work, we used computational and molecular modeling studies to provide further insight into the isomer-dependent binding mode and interaction of the carborane-containing derivatives of indomethacin methyl ester (R-2, S-2, and 3o,m,p in Figure 1) with COX-2. The capability of docking and QM/MM calculations to reproduce experimentally observed binding affinity trends for the carborane ligands and to predict plausible binding modes is also discussed.

RESULTS First, the enantiomers of 2 were docked into the COX-2:2 crystal structure (PDB ID: 4Z0L). These molecular docking calculations predicted two distinct binding modes (Figure 2). Pose A corresponds to the experimental binding mode, whereas pose B has the indole moiety rotated ~180° compared to pose A. Based on the calculated percentage populations from the ensemble of docking solutions, pose A was predicted to be more favorable than pose B for both enantiomers. The remaining poses were grouped into clusters with insignificant percentage populations (R-2: 2%, 3%, 1%, 1% and 2%; S-2: 1%, 2% and 1%). The pose A average root-mean-square deviation (RMSD) for enantiomer R-2 is considerably higher than for S-2 (1.6 Å for R-2 and 0.3 Å for S-2, Figure 2). Furthermore, pose A with enantiomer S-2 clearly reproduces the crystallographic binding mode with a preferred orientation for the nido-carborate cluster. On the other hand, pose A with enantiomer R6


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2 displays multiple, degenerate orientations for the nido-carborate cluster. The RMSD calculated for only the carborane cluster heavy atoms was 2.0 Å for R-2 and 0.2 Å for S-2. These docking calculations and comparisons with the crystallographic data strongly suggest that enantiomer S-2 binds preferentially to COX-2. The alternative binding mode pose B is reminiscent of the COX-1 binding mode determined experimentally for the S enantiomer of α-substituted indomethacin ethanolamide.8 In contrast, the corresponding R enantiomers of these ethanolamides bind to COX-1 analogous to the parent indomethacin. Whereas the S enantiomer inhibits both COX-1 and COX-2, the corresponding R enantiomer is a COX-2-selective inhibitor.7,8 Consequently, it is plausible that the binding affinity and binding mode of 2 depends on the planar chirality of the nido-dicarbaborate cluster.

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Figure 2. A) R-2 pose A; B) R-2 pose B; C) S-2 pose A; D) S-2 pose B. Stereo view of the poses of R-2 (top) and S-2 (bottom) docked into the COX-2:2 structure (PDB ID: 4Z0L) with the corresponding lowest binding energies, percentage populations and average root-mean-square 9



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deviation for each group. The structure with the lowest estimated binding energy is shown with green carbon atoms (stick representation). Structures with higher estimated binding energy are shown with orange carbon atoms (wire representation). COX-2 carbon atoms: gray; carborane carbon atoms are shown as balls; B: sienna; O: red; N: blue.

Whereas the docking results for pose A agree better with the crystallographic data, we cannot exclude the possibility that pose B is also a valid binding mode. In particular, the predicted binding energy for the R-2 enantiomer is lower for pose B than pose A, even though the computed population percentages strongly favor pose A. Full MD simulations for each enantiomer in each starting pose may help to resolve these apparently contradictory results observed for the rigid docking

calculations.

Previous

MD

studies

with

the

COX-2-selective

inhibitor

1-

phenylsulfonamide-3-trifluoromethyl-5-p-bromophenylpyrazole (SC-558) identified an alternative binding mode not characterized during initial X-ray structure refinement.33 This alternative SC-558 pose was stable during MD simulations and helped to explain the time-dependent inhibition characteristics observed for SC-558 and related COX inhibitors. However, we could not use MD simulations to explore the alternative binding pose for 2 because suitable carborane force field parameters are not readily available at present, as discussed above. We next used QM/MM calculations to examine detailed energetics for both R-2 and S-2 enantiomer complexes with COX-2, and to further investigate the possible basis for the enantiomer selectivity. Docked complexes were optimized using a QM/MM protocol similar to the one used previously to study carborane−protein interactions.32 The QM zone contains the inhibitor and only those COX-2 residues that interact directly with the nido-dicarbaborate moiety of the inhibitor (see Computational Methods section for details). The calculated inhibitor−COX-2 interaction energies 10


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(∆Gint) indicate that the S enantiomer of 2 binds preferentially to COX-2 (Figure 3). The lengths of the computed B−H···H−C dihydrogen bonds are between 2.0 and 2.3 Å. Including additional COX-2 residues that interact with the inhibitor indole moiety and ester group in the QM zone did not alter the computed binding preference for the R-2 versus S-2 enantiomers, suggesting that our definition of the QM zone has not biased the results in any significant way (see Supporting Information).

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Figure 3. Stereo view of the optimized QM zone geometries of A) R-2 and B) S-2 in COX-2. ∆Gint = Inhibitor−COX-2 interaction energy. COX-2, C: gray. Ligand, C: green, B: sienna, O: red, N: blue, S: yellow. Hydrogen atoms are omitted for clarity.

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Energy decomposition analysis revealed that the R120 residue of COX-2 contributes most to the nido-dicarbaborate/enzyme interaction energy ∆Gint (Figure 4), corresponding with the extensive interactions between R120 and the inhibitor. An ionic interaction forms between the positively charged R120 guanidino group and the negatively charged nido cluster. Two B–H groups form dihydrogen bonds with R120 Cγ and Cδ hydrogen atoms, while the carbonyl oxygen atom of S-2 forms a conventional hydrogen bond with an R120 Nε hydrogen atom (Figure 5). Figure 4 depicts the interaction energy contribution for each COX-2 residue with the nidodicarbaborate moiety for both R-2 and S-2 complexes, and the overall trend clearly favors the S-2 enantiomer. The largest ∆∆Gint difference is observed for V349; this interaction significantly favors the binding of S-2 over R-2 (∆∆Gint: –1.10 and 0.75 kcal mol–1, respectively). Only residue A527 displays a preferable interaction of COX-2 with enantiomer R-2 versus S-2 (∆∆Gint: –3.13 and –2.14 kcal mol–1, respectively). A527 interacts mainly with the indole CH3 moiety of 2. The differences in ∆∆Gint result from the different orientations of the indole CH3 group in R-2 versus S-2. The overall differences in ∆∆Gint most probably arise from the planar chirality and the different orientation of the nido-dicarbaborate moieties of R-2 and S-2, and residues I345 and V349 appear to be particularly sensitive to the specific nido-dicarbaborate substituent orientation (Figure 3 and Figure 4).

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Figure 4. Contribution of COX-2 residues to the interaction energy ∆Gint of R-2 (blue) and S-2 (orange).

Figure 5. Stereo view of the interactions between S-2 and COX-2 R120. COX-2 R120, C: gray, N: blue, H: white. Ligand, C: green, B: sienna, O: red, N: blue, S: yellow, H: white. Distances are shown in Å.

Next, the closo-carborane derivatives 3o,m,p were docked into the COX-2:2 crystal structure (PDB ID: 4Z0L). These molecular docking results revealed pose A as the main binding mode 14


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(Figure 6). An orientation similar to pose B of 2 has also been determined for 3o,m,p, albeit with smaller percentage populations (3o: 9%, 3m: 10% and 3p 21%). The remaining 3o,m,p poses were grouped into clusters with small percentage populations (3o: 1%, 2%, 4%, 8%, 1% and 3%; 3m: 3%, 4%, 6%, 1% and 4%; 3p: 1%, 8%, 1% and 8%). Furthermore, pose A of 3 is similar to the experimental binding mode of 2, enabling the same interactions with COX-2 that were found in the 4Z0L crystal structure. The ester group in 3 interacts with S530, the carbonyl group in 3 forms polar interactions with R120 and the closo carborane cluster protrudes into the hydrophobic sub-pocket that has been observed to specifically open up during the binding of 2. The calculated pose A binding free energies present a decreasing trend 3o > 3m > 3p, in agreement with the experimentally observed inhibitory activities of these derivatives. However, it should be noted that the computed binding energy differences for the ligands are smaller than the standard error for these calculations (see Computational Methods section for details). In the 4Z0L structure, the ortho-carborane cluster of 3o appears to have a preferred orientation with the C–H group in the closo cluster pointing towards V116 (Figure 7). On the other hand, no preferred orientation was predicted for the metacarborane moiety of 3m. The C–H group in the closo cluster of 3m points either towards V116, M113 or I345. Furthermore, the carborane cluster atoms of 3m fluctuate considerably more than those of 3o (Figure 7), i.e., the docking calculations do not yield a discrete, well-defined docking pose for compound 3m. These differences may further indicate that 3o binds more favorably than 3m to COX-2 and suggest that the position of the mildly acidic carborane C–H protons may play an important role in influencing the relative COX inhibitory activity of 3o,m,p. A higher exposure of the C–H protons to the surrounding hydrophobic pocket correlates with the loss of activity, as suggested for the carborane derivatives of the local anesthetic lidocaine.24

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Figure 6. Stereo view of the docked poses of A) 3o, B) 3m, and C) 3p in the COX-2:2 structure (PDB ID: 4Z0L) with the corresponding lowest binding energies, percentage populations, and average RMSD for each group. The structure with the lowest estimated binding energy is shown with green carbon atoms (stick representation). Structures with higher estimated binding energy are shown with orange carbon atoms (wire representation). COX-2 carbon atoms: gray; carborane carbon atoms are shown as balls; B: sienna, O: red, N: blue.

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Figure 7. Stereo views illustrating the docked orientation of the carborane cluster of A) 3o and B) 3m with the corresponding average RMSDs calculated only for the carborane cluster atoms of 0.8 Å and 1.3 Å, respectively. COX-2 carbon atoms: gray; carborane carbon atoms are shown as orange balls; B: sienna, O: red, N: blue.

Since the docking studies correctly predict 3o as the most potent COX-2 inhibitor from the three closo-carborane-containing derivatives of indomethacin methyl ester, it appears that the available boron parameters and the AutoDock protocol utilized in this work may be useful for docking 18


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prediction purposes. Nevertheless, the docking parameters probably can be further optimized to give more reliable binding free energies. In a previous study,12 we demonstrated that molecular docking calculations were able to predict the experimental binding mode of 2 using a COX-2 structure complexed with celecoxib (PDB ID: 3LN1).34 This result is significant, as the COX-2:celecoxib crystal structure (PDB ID: 3LN1) and the COX-2:2 crystal structure (PDB ID: 4Z0L) used in the current study exhibit notable structural differences in the binding site region, particularly the rotation of the side chain of L531 that opens a hydrophobic sub-pocket into which the nido-dicarbaborate cluster of ligand 2 binds (see Supporting Information for details). Using these two distinctly different crystal structures for docking is an attempt to take into account the possible impact of different binding site conformations. Molecular docking calculations for 3o,m,p using the COX-2:celecoxib crystal structure (PDB ID: 3LN1) gave quite similar results to the docking calculations based on the COX-2:2 crystal structure (PDB ID: 4Z0L). These molecular docking simulations also revealed pose A as the main binding mode for 3o, capturing the same ligand-COX-2 interactions as the calculations using the COX-2:2 crystal structure (PDB ID: 4Z0L, Figure 6) and as found in the experimental binding mode of 2 (see Supporting Information). For 3m and 3p, the docking calculations using the COX-2:celecoxib crystal structure could not clearly distinguish between three different binding modes (see Supporting Information). Thus, it appears that the predicted binding mode for ligand 3o is not biased by the rigid receptor models used in the docking calculations. In order to examine energetic details for the binding of compounds 3o,m,p, QM/MM calculations were performed for each complex (see Computational Methods for details). The poses with the lowest energy predicted by the docking calculations with the 4Z0L target were used as starting structures. The QM/MM calculations show clearly that isomer 3p binds much less tightly to COX-2 19



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than either 3o or 3m. However, the computed binding energies for 3o and 3m are nearly identical (Figure 8). Extension of the QM zone to include additional COX-2 residues did not yield clearer binding energy trends for these three isomers (see Supporting Information). It should be noted that the QM/MM calculations were performed only for the lowest energy docked pose of 3o,m,p, and did not account for the different possible orientations of the carborane clusters. The docking simulations indicated that the different orientation of the carborane clusters and of the mildly acidic C–H protons may play an important role in influencing the relative COX inhibitory activity of 3o,m,p. According to the docked conformations, the acidic CH group of 3o points out of the hydrophobic pocket, whereas the acidic CH groups of 3m and 3p are located within the hydrophobic pocket, and may thereby destabilize the binding of these two derivatives. The different electronic properties of the closo-carborane moieties of 3o,m,p may play a role in modulating their COX-2 inhibition activity as well. The sum of the BH group partial atomic charges increases in the order ortho < meta < para (see Supporting Information), and the strength of the B–H···H–C dihydrogen bonds may also decrease in the order ortho > meta > para. The B–H···H–C dihydrogen bond patterns between 3o,m,p and COX-2 are similar to the ones observed for COX-2:2 and the computed distances are in the 1.9-2.3 Å range for 3o, in the 2.1-2.3 Å range for 3m, and in the 1.9-2.3 Å range for 3p.

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Figure 8. Stereo view of the optimized QM zone geometries of A) 3o, B) 3m, and C) 3p in COX-2. ∆Gint = Inhibitor−COX-2 interaction energy. COX-2, C: gray; ligand, C: green, B: sienna, O: red, N: blue, S: yellow. Hydrogen atoms are omitted for clarity.

DISCUSSION Computational and molecular modeling studies and comparisons with the crystallographic data suggest that the S enantiomer of compound 2 binds preferentially to COX-2. The molecular docking calculations revealed two distinct binding modes for the enantiomers, and at this point we cannot exclude the possibility that the R enantiomer may bind in an alternative pose. Docking studies using two distinct COX-2 crystal structures suggested a binding mode for compound 3o similar to the orientation of the ligand observed in the COX-2:2 crystal structure. The ortho-carborane cluster of 3o may adopt a more favorable orientation than the meta-carborane 22


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moiety of 3m. The C–H group in the closo cluster of 3o points mainly towards V116, while the closo cluster of 3m points either towards V116, M113, or I345 (Figure 7). The orientation of the ligands during the docking calculations may be influenced by the rigid receptor geometry, and introducing receptor flexibility into the docking calculations may help to confirm or disprove a preferred carborane cluster orientation. The QM/MM geometry optimizations, like all minimization procedures, have a relatively small radius of convergence and cannot fully account for the dynamic movement of the ligands and surrounding receptor residues during minimization. Full MD simulations could help to verify the relative stability of the docked poses and may even enable the prediction of the COX-1/COX-2 selectivity, as observed in previous studies.35,36,37 However, the lack of appropriate carborane force field parameters precludes these simulations at present. The mildly acidic carborane C–H protons may play a major role in influencing the COX-2 inhibition activity of 3o,m,p, as observed previously for carborane-containing derivatives of lidocaine.24 Less exposure of the acidic carborane C–H protons to the hydrophobic pocket may correlate with higher COX-2 inhibition. In the case of 2 and 3o, the acidic CH groups point out of the hydrophobic pocket. In contrast, the acidic CH groups of 3m and 3p are positioned inside the hydrophobic pocket and may thereby destabilize the binding of these two derivatives, resulting in a low COX inhibitory activity. It should be noted, that the acidity of the cluster C–H group, indicated by a positive partial charge, increases in the order of 3o < 3m < 3p (see Supporting Information for details).

CONCLUSIONS Carborane-containing drug molecules have increasingly become the focus of molecular modeling studies and drug design projects with the increased utilization of carboranes as pharmacophores. 23



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Here, we report studies to assess the predictive capability of the computational tools available for the study of carborane-containing drug molecules by modeling the interactions of indomethacin methyl ester derivatives with the COX-2 enzyme. Docking and QM/MM calculations for inhibitor/COX-2 complexes suggest that compound S-2 binds more favorably to COX-2 than compound R-2. A careful evaluation of docking results identified compound 3o as the most potent COX-2 inhibitor from the three closo-carborane-containing derivatives of indomethacin methyl ester, in agreement with experiment. Overall, docking simulations conducted with the available boron parameters gave encouraging results that are in qualitative agreement with available experimental data. However, inclusion of full receptor flexibility in the molecular docking calculations may yield more definitive results, and this is best accomplished utilizing full MD simulations. For this purpose, appropriate carborane force field parameters need to be developed first. In the meantime, the molecular docking and QMMM energy calculations reported herein provide insight that may help explain why enantiomer S-2 and compound 3o are better inhibitors than their related isomers.

COMPUTATIONAL METHODS: Docking studies: Ligand structures were constructed with GaussView 5.38 Ligand geometries were optimized with Gaussian 09 at the HF/6-31G(d,p) level of theory.39 The atomic charges for each ligand were derived using the RESP procedure40,41,42 with Gaussian 09 and the antechamber program of the AmberTools13 package.43 The RESP charges of the hydrogen atoms in the closocarborane clusters support the possibility of the formation of B–H···H–C dihydrogen bonds and B– H···Na+ bridges (see Supporting Information). This is not the case for partial charges derived from Mulliken population analysis, nor for natural atomic charges.15 The crystal structures for COX-2 24


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complexed with the COX-2-selective inhibitor celecoxib (PDB ID: 3LN1)34 and compound 2 (PDB ID: 4Z0L)12 were downloaded from the Protein Data Bank (PDB). All ligands and non-standard residues except for the heme groups, and all water molecules were removed with the UCSF Chimera package.44 One monomer of COX-2 was prepared for docking with AutoDock Tools 1.5.6.45 After adding the missing hydrogen atoms to the selected protein structures, Gasteiger charges were assigned to each atom of the macromolecules, since AutoDock4 scoring function was calibrated using Gasteiger partial charges on both the ligand and the macromolecule. All histidine, lysine and arginine residues were set up in their protonated state, whereas all aspartic acid and glutamic acid residues were set up in their deprotonated state. All polar hydrogen atoms were kept and all nonpolar hydrogen atoms were merged in order to conform to the AutoDock atom types. The optimized geometries of the ligands were prepared for docking. Ligand nonpolar hydrogens (including carborane C–H protons) were merged to conform to the AutoDock atom types, and all of the torsion angles within the carborane clusters were set to non-rotatable. A new atom type (B) was defined for the boron atoms, utilizing the force field parameters reported by Tiwari et al. for docking of carborane-containing ligands.25 The docking area was defined using AutoGrid 4.2.5.45 A 60×44×44 Å three-dimensional affinity grid with 0.375 Å grid point spacing was placed around the COX-2 active site. Docking was performed with AutoDock 4.2.5.1.45 The Lamarckian genetic algorithm (LGA) was selected for the ligand conformational search.46 Parameters used for LGA include: population size of 150 individuals, maximum of 4×106 energy evaluations, maximum of 27,000 generations, one top individual to survive to the next generation automatically, mutation rate of 0.02, crossover rate of 0.8, and 100 docking runs with random initial positions and conformations. The probability of performing a local search on an individual in the population was set to 0.06 and the maximum number of iterations per local search was set to 300. The final docked 25



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conformations were grouped using a tolerance of 1.5 Å RMSD, and the cluster populations were interpreted as percentages. The setup of the docking protocols and the analysis of the results were done with AutoDock Tools 1.5.6.45 The standard error of the AutoDock free energy scoring function was 2–3 kcal mol–1.45 Combined quantum mechanics and molecular mechanics (QM/MM) calculations: The COX-2:2 crystal structure coordinates were used as the starting geometries in the QM/MM calculations for the enantiomers of compound 2. For compounds 3o,m,p, the poses obtained from docking to the COX-2:2 crystal structure (PDB ID: 4Z0L)19 were used as starting coordinates. Hydrogen atoms were automatically added with the UCSF Chimera package44 and manually with GaussView 5.38 Force field parameters were assigned using the leap program of the AmberTools13 package.43 The QM/MM calculations were performed with the sander module of AMBER1247 and with the ORCA 3.0.3 program package48 using the QM/MM interface of Götz et al.49 The small QM zone contained the ligand and fragments of those COX-2 residues that interact directly with the carborane moiety of the ligands (a total of 162 COX-2 atoms besides the ligand atoms). The large QM zone contained the ligand, the COX-2 residue fragments included in the small QM zone and additionally fragments of those COX-2 residues that interact with the inhibitor indole moiety and ester group (a total of 354 COX-2 atoms besides the ligand atoms). Whenever possible, the MM-QM link hydrogen atoms were placed along non-polar C−C bonds. The docked complexes were minimized using the ff03.r1 force field50 for the MM zone and the HF-3c51 method for the QM zone. The positions of the bridging protons for the two enantiomers of 2 were not predicted correctly by the HF-3c method and had to be adjusted manually prior to further geometry optimization. The resulting structures for each COX2:inhibitor complex were further optimized with the BLYP functional52,53,54 and the SVP basis set55-57 as the QM method. In these subsequent geometry optimizations, density fitting techniques, 26


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also called resolution-of-identity approximation (RI),58-63,56,57 were used, along with dispersion corrections.64,65 All minimizations were run until the RMS gradient was less than 0.5 kcal/mol/Å. The QM zone for each geometry-optimized complex was extracted and the resulting geometries were used for single point QM energy calculations. The interaction energies between the ligands and COX-2 residues were calculated with the TPSS functional66 and the TZVP basis set.55 These calculations also employed the RI approximation and dispersion corrections. Solvent effects (i.e., water) were modeled with the conductor-like screening model (COSMO), as implemented in ORCA. A similar QM/MM protocol was used previously to study carborane−protein interactions.32

SUPPORTING INFORMATION The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jcim. Carborane cluster boron atom parameters used for docking (S1). Tables with the partial charges on the carborane cluster atoms obtained with various methods (S2). Optimized QM zone geometries of R-2 and S-2 including additional COX-2 fragments (Figure S3). Optimized QM zone geometries of 3o,m,p including additional COX-2 fragments (Figure S4). Comparison of the COX 2:2 (PDB ID: 4Z0L) and COX 2:celecoxib (PDB ID: 3LN1) crystal structures (Figure S5). Docked poses of 3o,m,p, in the COX-2:celecoxib (PDB ID: 3LN1) structure (Figures S6–S8). AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail: [email protected]

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ORCID Menyhárt-Botond Sárosi: 0000-0003-4222-0717 Wilma Neumann: 0000-0002-1728-5140 Terry P. Lybrand: 0000-0002-2248-104X Evamarie Hey-Hawkins: 0000-0003-4267-0603 Present Address †

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (United

States) Notes The authors declare no competing ﬁnancial interest.

ACKNOWLEDGEMENTS This work was supported by the European Union, the Free State of Saxony and the German Research Foundation (DFG, SA 2902/2-1 and HE 1376/38-1). Molecular graphics were rendered using UCSF Chimera.44 ABBREVIATIONS COX, cyclooxygenase; LJ, Lennard-Jones; MM, molecular mechanics; MD, molecular dynamics; DFT-D, dispersion-corrected density functional theory; QM, quantum mechanics; RMSD, rootmean-square deviation; RI, resolution-of-identity.

REFERENCES 28


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Abstract Graphics

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Molecular Modeling of the Interactions between Carborane

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