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Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3)

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Abstract

Tyrosine kinases are a wide family of targets with strong pharmacological relevance. These proteins undergo large-scale conformational motions able to inactivate them. By the end of one of these structural processes, a new cavity is opened allowing the access to a specific type of inhibitors, called type II. The kinase domain of fibroblast growth factor receptor 3 (FGFR3) falls into this family of kinases. We describe here, for the first time, its inactivation process through target molecular dynamics. The transient cavity, at the crossroad between the DFGout and Cα helix out inactivation is herein explored. Molecular docking calculations of known ligands demonstrated that type II inhibitors are able to interact with this metastable transient conformation of FGFR3 kinase. Besides, supplemental computations were conducted and clearly show that type II inhibitors drive the kinase inactivation process through specific stabilization with the DFG triad. This induced-fit effect of type II ligands toward FGFR3 might be extrapolated to other kinase systems and provides meaningful structural information for future drug developments.

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References

  1. Mannig G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934

    Article  Google Scholar 

  2. Hanks SK (2003) Genomic analysis of the eukaryotic protein kinase superfamily: a perspective. Genome Biol 4:111

    Article  Google Scholar 

  3. Cohen P (2002) Protein kinases—the major drug targets of the twenty-first century? Nat Rev Drug Discov 1:309–315

    Article  CAS  Google Scholar 

  4. Zuccotto F, Ardini E, Casale E, Angiolini M (2010) Through the “gatekeeper door”: exploiting the active kinase conformation. J Med Chem 53:2681–2694

    Article  CAS  Google Scholar 

  5. Shan Y, Seeliger MA, Eastwood MP, Frank F, Xu H, Jensen MØ, Dror RO, Kuriyan J, Shaw DE (2009) A conserved protonation-dependent switch controls drug binding in the Abl kinase. Proc Natl Acad Sci USA 106:139–144

    Article  CAS  Google Scholar 

  6. Johnson LN, Lowe ED, Noble ME, Owen D (1998) The eleventh Datta lecture. The structural basis for substrate recognition and control by protein kinases. FEBS Lett 430:1–11

    Article  CAS  Google Scholar 

  7. Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 209:275–282

    Article  Google Scholar 

  8. Lin Y-L, Roux B (2013) Computational analysis of the binding specificity of Gleevec to Abl, c-Kit, Lck, and c-Src tyrosine kinases. J Am Chem Soc 135:14741–14753

    Article  CAS  Google Scholar 

  9. Lin Y-L, Meng Y, Jiang W, Roux B (2013) Explaining why Gleevec is a specific and potent inhibitor of Abl kinase. Proc Natl Acad Sci USA 110:1664–1669

    Article  CAS  Google Scholar 

  10. Lin Y-L, Meng Y, Huang L, Roux B (2014) Computational study of Gleevec and G6G reveals molecular determinants of kinase inhibitor selectivity. J Am Chem Soc 136:14753–14762

    Article  CAS  Google Scholar 

  11. Shukla D, Meng Y, Roux B, Pande VS (2014) Activation pathway of Src kinase reveals intermediate states as targets for drug design. Nat Commun 5:3397

    Article  Google Scholar 

  12. Levinson NM, Kuchment O, Shen K, Young Ma, Koldobskiy M, Karplus M, Cole Pa, Kuriyan J (2006) A Src-like inactive conformation in the abl tyrosine kinase domain. PLoS Biol 4:e144

    Article  Google Scholar 

  13. Rousseau F, El Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le Merrer M, Munnich A, Bonaventure J (1996) Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TDI). Hum Mol Genet 5:509–512

    Article  CAS  Google Scholar 

  14. Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254

    Article  CAS  Google Scholar 

  15. Le Merrer M, Rousseau F, Legeai-Mallet L, Landais JC, Pelet A, Rozet JM, Bonaventure J, Sanak M, Weissenbach J, Stoll C, Munnich A, Maroteaux P (1994) A gene for achondroplasia–hypochondroplasia maps to chromosome 4p. Nat Genet 6:318–321

    Article  Google Scholar 

  16. Tanaka N, Katsuma N, Horikawa R, Tanaka T (2003) The comparison of the effects of short-term growth hormone treatment in patients with achondroplasia and with hypochondroplasia. Endocrinol J 50:69–75

    CAS  Google Scholar 

  17. Yasui N, Kawabata H, Kojimoto H, Ohno H, Matsuda S, Araki N, Shimomura Y, Ochi T (1997) Lengthening of the lower limbs in patients with achondroplasia and hypochondroplasia. Clin Orthop Relat Res 344:298–306

    Article  Google Scholar 

  18. Tak-Tak L, Barbault F, Maurel F, Busca P, Le Merrer Y (2011) Synthesis of purin-2-yl and purin-6-yl-aminoglucitols as C-nucleosidic ATP mimics and biological evaluation as FGFR3 inhibitors. Eur J Med Chem 46:1254–1262

    Article  CAS  Google Scholar 

  19. Jonquoy A, Mugniery E, Benoist-Lasselin C, Kaci N, Le Corre L, Barbault F, Girard A-L, Le Merrer Y, Busca P, Schibler L, Munnich A, Legeai-Mallet L (2012) A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function FGFR3 mouse model. Hum Mol Genet 21:841–851

    Article  CAS  Google Scholar 

  20. Han S, Mistry A, Chang JS, Cunningham D, Criffor M, Bonnette PC, Wang H, Chrunyk BA, Aspnes GE, Walker DP, Brosius AD, Buckbinder L (2009) Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique DFG-out conformation and enables inhibitor design. J Biol Chem 8:13193–13201

    Article  Google Scholar 

  21. Vogtherr M, Saxena K, Hoelder S, Grimme S, Betz M, Schieborn U, Pescatore B, Robin M, Delarbe L, Langer T, Wendt KU, Schwalbe H (2006) NMR characterization of kinase p38 dynamics in free and ligand bound form. Angew Chem Int Ed 45:993–997

    Article  CAS  Google Scholar 

  22. Schrödinger: Maestro suite 2011. LLC New York, NY (2011)

  23. Wang J, Wolf R, Caldwell J, Kollman P, Case D (2004) Development and testing of a general amber force field. J Comput Chem 25:1157–1174

    Article  CAS  Google Scholar 

  24. Case D, Darden T, Cheatham T, Simmerling C, Wang J, Duke L, Luo R, Crowley M, Walker R, Zhang W, Merz K, Wang B, Hayik S, Roitberg A, Seabra G, Kolossvary I, Wong K, Paesani F, Vanicek J, Wu X, Brozell S, Steinbrecher T, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Gui G, Mathews D, Seetin M, et al (2010) AMBER v11. 2010

  25. Bocharov EV, Lesovoy DM, Goncharuk SA, Goncharuk MV, Hristova K, Arseniev AS (2013) Structure of FGFR3 transmembrane domain dimer: implications for signaling and human pathologies. Structure 21:2087–2093

  26. Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, Eliseenkova AV, Green D, Schlessinger J, Hubbard SR (1998) Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J 17:5896–5904

    Article  CAS  Google Scholar 

  27. Bae JH, Boggon TJ, Tomé F, Mandiyan V, Lax I, Schlessinger J (2010) Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells. Proc Natl Acad Sci USA 107:2866–2871

    Article  CAS  Google Scholar 

  28. Mohammadi M (1996) Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism. Cell 86:577–587

    Article  CAS  Google Scholar 

  29. Ravindranathan KP, Mandiyan V, Ekkati AR, Bae JH, Schlessinger J, Jorgensen WL (2010) Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening. J Med Chem 53:1662–1672

    Article  CAS  Google Scholar 

  30. Eathiraj S, Palma R, Hirschi M, Volckova E, Nakuci E, Castro J, Chen C-R, Chan TCK, France DS, Ashwell MA (2011) A novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited kinases: discovery of ATP-independent inhibitors of fibroblast growth factor receptor. J Biol Chem 286:20677–20687

    Article  CAS  Google Scholar 

  31. Ibrahimi OA, Eliseenkova AV, Plotnikov AN, Yu K, Ornitz DM, Mohammadi M (2001) Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc Natl Acad Sci USA 98:7182–7187

    Article  CAS  Google Scholar 

  32. Chen H, Ma J, Li W, Eliseenkova AV, Xu C, Neubert TA, Miller WT, Mohammadi M (2007) A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol Cell 27:717–730

    Article  Google Scholar 

  33. Lambert C, Leonard N, De Bolle X, Depiereux E (2002) ESyPred3D: prediction of proteins 3D structures. Bioinformatics 18:1250–1256

    Article  CAS  Google Scholar 

  34. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: An N log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  35. Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis J, Dror RO, Shaw DE (2010) Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 78:1950–1958

    CAS  Google Scholar 

  36. Jakalian A, Bush B, Jack D, Bayly C (2000) Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method. J Comput Chem 21:132–146

    Article  CAS  Google Scholar 

  37. Jakalian A, Jack D, Bayly C (2002) Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. J Comput Chem 23:1623–1641

    Article  CAS  Google Scholar 

  38. Ryckaert J, Ciccotti G, Berendsen H (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of N-alkanes. J Comput Phys 23:327–341

    Article  CAS  Google Scholar 

  39. Uberuaga BP, Anghel M, Voter AF (2004) Synchronization of trajectories in canonical molecular-dynamics simulations: observation, explanation, and exploitation. J Chem Phys 120:6363–6374

    Article  CAS  Google Scholar 

  40. Pastor RW, Brooks BR, Szabo A (1988) An analysis of the accuracy of Langevin and molecular dynamics algorithms. Mol Phys 65:1409–1419

    Article  Google Scholar 

  41. Schlitter I, Engels M, Krüger P (1994) Targeted molecular dynamics: a new approach for searching pathways of conformational transition. J Mol Graph 12:84–89

    Article  CAS  Google Scholar 

  42. Karplus M, Kuriyan J (2005) Molecular dynamics and protein function. Proc Natl Acad Sci USA 102:6679–6685

    Article  CAS  Google Scholar 

  43. Li Y, Barbault F, Delamar M (2013) Targeted molecular dynamics (TMD) of the full-length KcsA potassium channel: on the role of the cytoplasmic domain in the opening process. J Mol Model 19:1651–1666

    Article  CAS  Google Scholar 

  44. Papaelo E, Mereghetti P, Fantucci P, Grandori R, De Goia L (2009) Free-energy landscape, principal component analysis, and structural clustering to identify representative conformations from molecular dynamics simulations: the myoglobin case. J Mol Graph Model 27:889–899

    Article  Google Scholar 

  45. Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D, Olson A (2009) AutoDock4 and AutoDock Tools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791

    Article  CAS  Google Scholar 

  46. Teixeira C, Serradji N, Maurel F, Barbault F (2009) Docking and 3D-QSAR studies of BMS-806 analogs as HIV-1 gp120 entry inhibitors. Eur J Med Chem 44:3524–3532

    Article  CAS  Google Scholar 

  47. Teixeira C, Barbault F, Rebehmed J, Liu K, Xie L, Lu H, Jiang S, Fan B, Maurel F (2008) Molecular modeling studies of N-substituted pyrrole derivatives–potential HIV-1 gp41 inhibitors. Bioorg Med Chem 16:3039–3048

    Article  CAS  Google Scholar 

  48. Koes D, Camacho C (2011) Pharmer: efficient and exact pharmacophore search. J Chem Inf Model 51:1307–1314

    Article  CAS  Google Scholar 

  49. Kollman P, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case D, Cheatham T (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897

    Article  CAS  Google Scholar 

  50. Aixiao L, Barbault F, Maurel F, Delamar M, Wang B (2008) Interaction mode and selectivity of the 2PU inhibitor with the CDK4 and CDK2 cyclin-dependant kinases: a molecular dynamics study. J Mol Struct (Thoechem) 849:62–75

    Article  Google Scholar 

  51. Barbault F, Maurel F (2012) Is inhibition process better described with MD(QM/MM) simulations? The case of urokinase type plasminogen activator inhibitors. J Comput Chem 33:607–616

    Article  CAS  Google Scholar 

  52. Aixiao L, Maurel F, Barbault F, Delamar M, Wang B, Zhou X, Wang P (2010) Molecular modeling study of binding site selectivity of TQMP to G-quadruplex DNA. Eur J Med Chem 45:983–991

    Article  Google Scholar 

  53. Barbault F, Ren B, Rebehmed J, Teixeira C, Luo Y, Smila-Castro O, Maurel F, Fan B, Zhang L, Zhang L (2008) Flexible computational docking studies of new aminoglycosides targeting RNA 16S bacterial ribosome site. Eur J Med Chem 43:1648–1656

    Article  CAS  Google Scholar 

  54. Gourmala C, Luo Y, Barbault F, Zhang Y, Ghalem S, Maurel F, Fan B (2007) Elucidation of the LewisX–LewisX carbohydrate interaction with molecular dynamics simulations: a glycosynapse model. J Mol Struct (Thoechem) 821:22–29

    Article  CAS  Google Scholar 

  55. Luo Y, Barbault F, Gourmala C, Zhang Y, Maurel F, Hu Y, Fan BT (2008) Cellular interaction through LewisX cluster: theoretical studies. J Mol Model 14:901–910

    Article  CAS  Google Scholar 

  56. Sitkoff D, Sharp K, Honig B (1994) Correlating solvation free energies and surface tensions of hydrocarbon solutes. Biophys Chem 51:397–403

    Article  CAS  Google Scholar 

  57. Sitkoff D, Lockhart D, Sharp K, Honig B (1994) Calculation of electrostatic effects at the amino terminus of an alpha helix. Biophys J 67:2251–2260

    Article  CAS  Google Scholar 

  58. Luo R, David L, Gilson M (2002) Accelarated Poisson Boltzmann calculations for static and dynamic systems. J Comput Chem 23:1244–1253

    Article  CAS  Google Scholar 

  59. Kottalam J, Case D (1990) Langevin modes of macromolecules: application to crambin and DNA hexamers. Biopolymers 29:1409–1421

    Article  CAS  Google Scholar 

  60. Teixeira C, Serradji N, Amroune S, Storck K (2013) Is the conformational flexibility of piperazine derivatives important to inhibit HIV-1 replication? J Mol Graph Model 44:91–103

    Article  CAS  Google Scholar 

  61. Berteotti A, Cavalli A, Branduardi D, Gervasio FL, Recanatini M, Parrinello M (2009) Protein conformational transitions: the closure mechanism of a kinase explored by atomistic simulations. J Am Chem Soc 131:244–250

    Article  CAS  Google Scholar 

  62. Gan W, Yang S, Roux B (2009) Atomistic view of the conformational activation of Src kinase using the string method with swarms-of-trajectories. Biophys J 97:L8–L10

    Article  Google Scholar 

  63. Filomia F, De Rienzo F, Menziani MC (2010) Insights into MAPK p38alpha DFG flip mechanism by accelerated molecular dynamics. Bioorg Med Chem 18:6805–6812

    Article  CAS  Google Scholar 

  64. Laine E, Chauvot de Beauchêne I, Perahia D, Auclair C, Tchertanov L (2011) Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms. PLoS Comput Biol 7:e1002068

    Article  CAS  Google Scholar 

  65. Jacobs MD, Caron PR, Hare BJ (2008) Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex. Proteins 70:1451–1460

    Article  CAS  Google Scholar 

  66. Kufareva I, Abagyan R (2008) Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states. J Med Chem 51:7921–7932

    Article  CAS  Google Scholar 

  67. Ribeiro JV, Tamames JAC, Cerqueira NMFSA, Fernandes PA, Ramos MJ (2013) Volarea—a bioinformatics tool to calculate the surface area and the volume of molecular systems. Chem Biol Drug Des 82:743–755

    Article  CAS  Google Scholar 

  68. Reaction biology corp. http://www.reactionbiology.com

  69. Lamers MB, Antson AA, Hubbard RE, Scott RK, Williams DH (1999) Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine. J Mol Biol 285:713–725

    Article  CAS  Google Scholar 

  70. Le Corre L, Girard A-L, Aubertin J, Radvanyi F, Benoist-Lasselin C, Jonquoy A, Mugniery E, Legeai-Mallet L, Busca P, Le Merrer Y (2010) Synthesis and biological evaluation of a triazole-based library of pyrido[2,3-d]pyrimidines as FGFR3 tyrosine kinase inhibitors. Org Biomol Chem 8:2164–2173

    Article  Google Scholar 

  71. Thomas M, Huang W-S, Wen D, Zhu X, Wang Y, Metcalf CA, Liu S, Chen I, Romero J, Zou D, Sundaramoorthi R, Li F, Qi J, Cai L, Zhou T, Commodore L, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Iuliucci J, Rivera VM, Sawyer TK, Dalgarno DC, Clackson T, Shakespeare WC (2011) Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett 21:3743–3748

    Article  CAS  Google Scholar 

  72. Choi HG, Ren P, Adrian F, Sun F, Lee HS, Wang X, Ding Q, Zhang G, Xie Y, Zhang J, Liu Y, Tuntland T, Warmuth M, Manley PW, Mestan J, Gray NS, Sim T (2010) A type-II kinase inhibitor capable of inhibiting the T315I “gatekeeper” mutant of Bcr-Abl. J Med Chem 53:5439–5448

    Article  CAS  Google Scholar 

  73. ChemAxon. http://www.chemaxon.com/product/pka.html

  74. Hu R, Barbault F, Maurel F, Delamar M, Zhang R (2010) Molecular dynamics simulations of 2-amino-6-arylsulphonylbenzonitriles analogues as HIV inhibitors: interaction modes and binding free energies. Chem Biol Drug Des 76:518–526

    Article  CAS  Google Scholar 

  75. Klepeis JL, Lindorff-Larsen K, Dror RO, Shaw DE (2009) Long-timescale molecular dynamics simulations of protein structure and function. Curr Opin Struct Biol 19:120–127

    Article  CAS  Google Scholar 

  76. http://en.wikipedia.org/wiki/Anton_(computer)

  77. Müller K, Faeh C, Diederich F (2007) Fluorine in pharmaceuticals: looking beyond intuition. Science 317:1881–1886

    Article  Google Scholar 

  78. Paulini R, Müller K, Diederich F (2005) Orthogonal multipolar interactions in structural chemistry and biology. Angew Chem Int Ed 44:1788–1805

    Article  CAS  Google Scholar 

  79. Grant BJ, Gorfe AA, McCammon JA (2010) Large conformational changes in proteins: signaling and other functions. Curr Opin Struct Biol 20:142–147

    Article  CAS  Google Scholar 

  80. Fabian M, Biggs W 3rd, Treiber D, Atteridge C, Azimioara M, Benedetti M, Carter T, Ciceri P, Edeen P, Floyd M, Ford J, Galvin M, Gerlach J, Grotzfeld R, Herrgard S, Insko D, Insko M, Lai A, Lélias J, Mehta S, Milanov Z, Velasco A, Wodicka L, Patel H, Zarrinkar P, Lockhart D (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329–336

    Article  CAS  Google Scholar 

  81. Agafonov RV, Wilson C, Otten R, Buosi V, Kern D (2014) Energetic dissection of Gleevec’s selectivity toward human tyrosine kinases. Nat Struct Mol Biol 21:848–853

    Article  CAS  Google Scholar 

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Acknowledgments

The China Scholarship Council is gratefully acknowledged for granting a Ph.D. scholarship to Yan LI. This work was granted access to the CINES (Centre Informatique National de l’Enseignement Supérieur, France) under the allocation c2013077022 made by GENCI (Grand Equipement National de Calcul Intensif). Financial support from the French agency ANR (Agence Nationale de la Recherche), under the program Grant name “ATAK”, is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Chemistry, Lanzhou University, Lanzhou, 730000, Gansu, People’s Republic of China

    Yan Li

  2. ITODYS, UMR CNRS 7086, Univ Paris Diderot, Sorbonne Paris Cité, 15 rue J-A. de Baïf, 75013, Paris, France

    Yan Li, Michel Delamar & Florent Barbault

  3. UMR 8601 CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, 45 rue des Saints-Pères, 75006, Paris, France

    Patricia Busca, Guillaume Prestat & Laurent Le Corre

  4. INSERM U781, Institut Imagine, Hôpital Necker-Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, 156 rue Vaugirard, Paris, France

    Laurence Legeai-Mallet

  5. School of Information Science and Engineering, Lanzhou University, Lanzhou, 730000, Gansu, People’s Republic of China

    RongJing Hu & Ruisheng Zhang

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  1. Yan Li
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Li, Y., Delamar, M., Busca, P. et al. Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3). J Comput Aided Mol Des 29, 619–641 (2015). https://doi.org/10.1007/s10822-015-9841-8

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