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Using halogen bonds to address the protein backbone: a systematic evaluation

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Abstract

Halogen bonds are specific embodiments of the sigma hole bonding paradigm. They represent directional interactions between the halogens chlorine, bromine, or iodine and an electron donor as binding partner. Using quantum chemical calculations at the MP2 level, we systematically explore how they can be used in molecular design to address the omnipresent carbonyls of the protein backbone. We characterize energetics and directionality and elucidate their spatial variability in sub-optimal geometries that are expected to occur in protein–ligand complexes featuring a multitude of concomitant interactions. By deriving simple rules, we aid medicinal chemists and chemical biologists in easily exploiting them for scaffold decoration and design. Our work shows that carbonyl–halogen bonds may be used to expand the patentable medicinal chemistry space, redefining halogens as key features. Furthermore, this data will be useful for implementing halogen bonds into pharmacophore models or scoring functions making the QM information available for automatic molecular recognition in virtual high throughput screening.

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References

  1. Hassel O (1970) Structural aspects of interatomic charge-transfer bonding. Science 170(3957):497–502. doi:10.1126/science.170.3957.497

    Article  CAS  Google Scholar 

  2. Pierangelo M, Franck M, Tullio P, Giuseppe R, Giancarlo T (2008) Halogen bonding in supramolecular chemistry. Angew Chem Int Ed 47(33):6114–6127. doi:10.1002/anie.200800128

    Article  Google Scholar 

  3. Auffinger P, Hays FA, Westhof E, Ho PS (2004) Halogen bonds in biological molecules. Proc Natl Acad Sci USA 101(48):16789–16794. doi:10.1073/pnas.0407607101

    Article  CAS  Google Scholar 

  4. Clark T, Hennemann M, Murray J, Politzer P (2007) Halogen bonding: the σ-hole. J Mol Mod 13(2):291–296. doi:10.1007/s00894-006-0130-2

    Article  CAS  Google Scholar 

  5. Murray J, Lane P, Politzer P (2009) Expansion of the σ-hole concept. J Mol Mod 15(6):723–729. doi:10.1007/s00894-008-0386-9

    Article  CAS  Google Scholar 

  6. Murray JS, Lane P, Politzer P (2007) A predicted new type of directional noncovalent interaction. Int J Quantum Chem 107(12):2286–2292. doi:10.1002/qua.21352

    Article  CAS  Google Scholar 

  7. Murray JS, Riley KE, Politzer P, Clark T (2010) Directional weak intermolecular interactions: σ-hole bonding. Aust J Chem 63(12):1598–1607. doi:10.1071/CH10259

    Article  CAS  Google Scholar 

  8. Politzer P, Lane P, Concha M, Ma Y, Murray J (2007) An overview of halogen bonding. J Mol Mod 13(2):305–311. doi:10.1007/s00894-006-0154-7

    Article  CAS  Google Scholar 

  9. Lu Y, Wang Y, Zhu W (2010) Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design. Phys Chem Chem Phys 12(18):4543–4551. doi:10.1039/B926326H

    Article  CAS  Google Scholar 

  10. Huber K, Brault L, Fedorov O, Gasser C, Filippakopoulos P, Bullock AN, Fabbro D, Trappe J, Schwaller J, Knapp S, Bracher F (2012) 7,8-dichloro-1-oxo-beta-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes. J Med Chem 55(1):403–413. doi:10.1021/jm201286z

    Article  CAS  Google Scholar 

  11. Fedorov O, Huber K, Eisenreich A, Filippakopoulos P, King O, Bullock AN, Szklarczyk D, Jensen LJ, Fabbro D, Trappe J, Rauch U, Bracher F, Knapp S (2011) Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. Chem Biol 18(1):67–76. doi:10.1016/j.chembiol.2010.11.009

    Article  CAS  Google Scholar 

  12. Hardegger LA, Kuhn B, Spinnler B, Anselm L, Ecabert R, Stihle M, Gsell B, Thoma R, Diez J, Benz J, Plancher J-M, Hartmann G, Banner DW, Haap W, Diederich F (2011) Systematic investigation of halogen bonding in protein–ligand interactions. Angew Chem Int Ed 50(1):314–318. doi:10.1002/anie.201006781

    Article  CAS  Google Scholar 

  13. Xu Z, Liu Z, Chen T, Wang Z, Tian G, Shi J, Wang X, Lu Y, Yan X, Wang G, Jiang H, Chen K, Wang S, Xu Y, Shen J, Zhu W (2011) Utilization of halogen bond in lead optimization: a case study of rational design of potent phosphodiesterase type 5 (PDE5) inhibitors. J Med Chem 54(15):5607–5611. doi:10.1021/jm200644r

    Article  CAS  Google Scholar 

  14. Hardegger LA, Kuhn B, Spinnler B, Anselm L, Ecabert R, Stihle M, Gsell B, Thoma R, Diez J, Benz J, Plancher JM, Hartmann G, Isshiki Y, Morikami K, Shimma N, Haap W, Banner DW, Diederich F (2011) Halogen bonding at the active sites of human cathepsin L and MEK1 kinase: efficient interactions in different environments. ChemMedChem 6(11):2048–2054. doi:10.1002/cmdc.201100353

    Article  CAS  Google Scholar 

  15. Wilcken R, Liu X, Zimmermann MO, Rutherford TJ, Fersht AR, Joerger AC, Boeckler FM (2012) Halogen-enriched fragment libraries as leads for drug rescue of mutant p53. J Am Chem Soc 134(15):6810–6818. doi:10.1021/ja301056a

    Article  CAS  Google Scholar 

  16. Joerger AC, Ang HC, Fersht AR (2006) Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc Natl Acad Sci USA 103(41):15056–15061. doi:10.1073/pnas.0607286103

    Article  CAS  Google Scholar 

  17. Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR (2008) Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci USA 105(30):10360–10365. doi:10.1073/pnas.0805326105

    Article  CAS  Google Scholar 

  18. Riley KE, Hobza P (2008) Investigations into the nature of halogen bonding including symmetry adapted perturbation theory analyses. J Chem Theory Comput 4(2):232–242. doi:10.1021/ct700216w

    Article  CAS  Google Scholar 

  19. Riley KE, Murray JS, Politzer P, Concha MC, Hobza P (2009) Br–O complexes as probes of factors affecting halogen bonding: interactions of bromobenzenes and bromopyrimidines with acetone. J Chem Theory Comput 5(1):155–163. doi:10.1021/ct8004134

    Article  CAS  Google Scholar 

  20. Wilcken R, Zimmermann MO, Lange A, Zahn S, Kirchner B, Boeckler FM (2011) Addressing methionine in molecular design through directed sulfur-halogen bonds. J Chem Theory Comput 7(7):2307–2315. doi:10.1021/Ct200245e

    Article  CAS  Google Scholar 

  21. Lu Y, Shi T, Wang Y, Yang H, Yan X, Luo X, Jiang H, Zhu W (2009) Halogen bonding, a novel interaction for rational drug design? J Med Chem 52(9):2854–2862. doi:10.1021/jm9000133

    Article  CAS  Google Scholar 

  22. Politzer P, Murray JS, Clark T (2010) Halogen bonding: an electrostatically-driven highly directional noncovalent interaction. Phys Chem Chem Phys 12(28):7748–7757. doi:10.1039/C004189K

    Article  CAS  Google Scholar 

  23. Politzer P, Murray JS, Lane P (2007) Sigma-hole bonding and hydrogen bonding: competitive interactions. Int J Quantum Chem 107(15):3046–3052. doi:10.1002/qua.21419

    Article  CAS  Google Scholar 

  24. Shields ZP, Murray JS, Politzer P (2010) Directional tendencies of halogen and hydrogen bonds. Int J Quantum Chem 110(15):2823–2832. doi:10.1002/qua.22787

    Article  CAS  Google Scholar 

  25. Voth AR, Khuu P, Oishi K, Ho PS (2009) Halogen bonds as orthogonal molecular interactions to hydrogen bonds. Nat Chem 1(1):74–79. doi:10.1038/nchem.112

    Article  CAS  Google Scholar 

  26. Weigend F, Ahlrichs R (2005) Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: design and assessment of accuracy. Phys Chem Chem Phys 7(18):3297–3305. doi:10.1039/B508541A

    Article  CAS  Google Scholar 

  27. Ahlrichs R, Bär M, Häser M, Horn H, Kölmel C (1989) Electronic structure calculations on workstation computers: the program system turbomole. Chem Phys Lett 162(3):165–169. doi:10.1016/0009-2614(89)85118-8

    Article  CAS  Google Scholar 

  28. TURBOMOLE v6.2 (2010), available from http://www.turbomole.com

  29. Peterson KA, Figgen D, Goll E, Stoll H, Dolg M (2003) Systematically convergent basis sets with relativistic pseudopotentials. II. Small-core pseudopotentials and correlation consistent basis sets for the post-d group 16–18 elements. J Chem Phys 119(21):11113–11123. doi:10.1063/1.1622924

    Article  CAS  Google Scholar 

  30. Feyereisen M, Fitzgerald G, Komornicki A (1993) Use of approximate integrals in ab initio theory. An application in MP2 energy calculations. Chem Phys Lett 208(5–6):359–363. doi:10.1016/0009-2614(93)87156-w

    Article  CAS  Google Scholar 

  31. Weigend F, Häser M, Patzelt H, Ahlrichs R (1998) RI-MP2: optimized auxiliary basis sets and demonstration of efficiency. Chem Phys Lett 294(1–3):143–152. doi:10.1016/s0009-2614(98)00862-8

    Article  CAS  Google Scholar 

  32. Hättig C (2005) Optimization of auxiliary basis sets for RI-MP2 and RI-CC2 calculations: core-valence and quintuple-z basis sets for H to Ar and QZVPP basis sets for Li to Kr. Phys Chem Chem Phys 7(1):59–66. doi:10.1039/B415208E

    Article  Google Scholar 

  33. Hellweg A, Hättig C, Höfener S, Klopper W (2007) Optimized accurate auxiliary basis sets for RI-MP2 and RI-CC2 calculations for the atoms Rb to Rn. Theor Chem Acc 117(4):587–597. doi:10.1007/s00214-007-0250-5

    Article  CAS  Google Scholar 

  34. Boys SF, Bernardi F (1970) The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Mol Phys 19(4):553–566. doi:10.1080/00268977000101561

    Article  CAS  Google Scholar 

  35. Grimme S (2003) Improved second-order Møller-Plesset perturbation theory by separate scaling of parallel- and antiparallel-spin pair correlation energies. J Chem Phys 118(20):9095–9102. doi:10.1063/1.1569242

    Article  CAS  Google Scholar 

  36. Dunning JTH (1989) Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen. J Chem Phys 90(2):1007–1023. doi:10.1063/1.456153

    Article  CAS  Google Scholar 

  37. Woon DE, Dunning JTH (1993) Gaussian basis sets for use in correlated molecular calculations. III. The atoms aluminum through argon. J Chem Phys 98(2):1358–1371. doi:10.1063/1.464303

    Article  CAS  Google Scholar 

  38. Peterson KA, Shepler BC, Figgen D, Stoll H (2006) On the spectroscopic and thermochemical properties of ClO, BrO, IO, and their anions. J Phys Chem A 110(51):13877–13883. doi:10.1021/jp065887l

    Article  CAS  Google Scholar 

  39. Weigend F, Kohn A, Hättig C (2002) Efficient use of the correlation consistent basis sets in resolution of the identity MP2 calculations. J Chem Phys 116(8):3175–3183. doi:10.1063/1.1445115

    Article  CAS  Google Scholar 

  40. Werner H-J, Knowles PJ, Lindh R, Manby FR, Schütz M, Celani P, Korona T, Rauhut G, Amos RD, Bernhardsson A, Berning A, Cooper DL, Deegan MJO, Dobbyn AJ, Eckert F, Hampel C, Hetzer G, Lloyd AW, McNicholas SJ, Meyer W, Mura ME, Nicklass A, Palmieri P, Pitzer R, Schumann U, Stoll H, Stone AJ, Tarroni R, Thorsteinsson T (2006) MOLPRO, version 2006.1, a package of ab initio programs; http://www.molpro.net

  41. Hobza P, Šponer J (2002) Toward true DNA base-stacking energies: MP2, CCSD(T), and complete basis set calculations. J Am Chem Soc 124(39):11802–11808. doi:10.1021/ja026759n

    Article  CAS  Google Scholar 

  42. Jurecka P, Sponer J, Cerny J, Hobza P (2006) Benchmark database of accurate (MP2 and CCSD(T) complete basis set limit) interaction energies of small model complexes, DNA base pairs, and amino acid pairs. Phys Chem Chem Phys 8(17):1985–1993. doi:10.1039/B600027D

    Article  CAS  Google Scholar 

  43. Halkier A, Helgaker T, Jørgensen P, Klopper W, Koch H, Olsen J, Wilson AK (1998) Basis-set convergence in correlated calculations on Ne, N2, and H2O. Chem Phys Lett 286(3–4):243–252. doi:10.1016/s0009-2614(98)00111-0

    Article  CAS  Google Scholar 

  44. DeLano WL (2008) The PyMOL molecular graphics system. DeLano Scientific LLC, Palo Alto, CA

    Google Scholar 

  45. Riley KE, Murray JS, Fanfrlik J, Rezac J, Sola RJ, Concha MC, Ramos FM, Politzer P (2012) Halogen bond tunability II: the varying roles of electrostatic and dispersion contributions to attraction in halogen bonds. J Mol Model. doi:10.1007/s00894-012-1428-x

  46. Hennemann M, Murray JS, Politzer P, Riley KE, Clark T (2012) Polarization-induced sigma-holes and hydrogen bonding. J Mol Mod 18(6):2461–2469. doi:10.1007/s00894-011-1263-5

    Article  CAS  Google Scholar 

  47. Darimont BD, Wagner RL, Apriletti JW, Stallcup MR, Kushner PJ, Baxter JD, Fletterick RJ, Yamamoto KR (1998) Structure and specificity of nuclear receptor–coactivator interactions. Genes Dev 12(21):3343–3356. doi:10.1101/gad.12.21.3343

    Article  CAS  Google Scholar 

  48. Horton JR, Sawada K, Nishibori M, Cheng X (2005) Structural basis for inhibition of histamine N-methyltransferase by diverse drugs. J Mol Biol 353(2):334–344. doi:10.1016/j.jmb.2005.08.040

    Article  CAS  Google Scholar 

  49. Tipparaju SK, Mulhearn DC, Klein GM, Chen Y, Tapadar S, Bishop MH, Yang S, Chen J, Ghassemi M, Santarsiero BD, Cook JL, Johlfs M, Mesecar AD, Johnson ME, Kozikowski AP (2008) Design and synthesis of aryl ether inhibitors of the Bacillus Anthracis enoyl-ACP reductase. ChemMedChem 3(8):1250–1268. doi:10.1002/cmdc.200800047

    Article  CAS  Google Scholar 

  50. De Moliner E, Brown NR, Johnson LN (2003) Alternative binding modes of an inhibitor to two different kinases. Eur J Biochem 270(15):3174–3181. doi:10.1046/j.1432-1033.2003.03697.x

    Article  Google Scholar 

  51. Battistutta R, Mazzorana M, Sarno S, Kazimierczuk Z, Zanotti G, Pinna LA (2005) Inspecting the structure-activity relationship of protein kinase CK2 inhibitors derived from tetrabromo-benzimidazole. Chem Biol 12(11):1211–1219. doi:10.1016/j.chembiol.2005.08.015

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany

    Rainer Wilcken, Markus O. Zimmermann, Andreas Lange & Frank M. Boeckler

  2. Wilhelm-Ostwald-Institut für Physikalische und Theoretische Chemie, Universität Leipzig, Linnéstr. 2, 04103, Leipzig, Germany

    Stefan Zahn

  3. MRC Laboratory of Molecular Biology, Hills Rd, Cambridge, CB2 0QH, UK

    Rainer Wilcken

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  1. Rainer Wilcken
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  2. Markus O. Zimmermann
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  3. Andreas Lange
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  4. Stefan Zahn
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  5. Frank M. Boeckler
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Correspondence to Frank M. Boeckler.

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Wilcken, R., Zimmermann, M.O., Lange, A. et al. Using halogen bonds to address the protein backbone: a systematic evaluation. J Comput Aided Mol Des 26, 935–945 (2012). https://doi.org/10.1007/s10822-012-9592-8

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  • DOI: https://doi.org/10.1007/s10822-012-9592-8

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