American Journal of Modeling and Optimization
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American Journal of Modeling and Optimization. 2015, 3(3), 68-86
DOI: 10.12691/ajmo-3-3-2
Open AccessReview Article

How Important is to Account for Water When Modeling Biomolecular Complexes?

María J. R. Yunta1,

1Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense, Madrid, Spain

Pub. Date: October 31, 2015

Cite this paper:
María J. R. Yunta. How Important is to Account for Water When Modeling Biomolecular Complexes?. American Journal of Modeling and Optimization. 2015; 3(3):68-86. doi: 10.12691/ajmo-3-3-2


Taking account of the presence of water molecules is sometimes crucial for free energy calculations to predict binding ability of molecules to receptors, a main subject for drug design. This mini-review seeks to identify the importance of knowing the influence of these molecules in such studies to better achieve correct predictions for drug candidates. Participation of some water molecules need to be considered in docking studies although they have been usually neglected.

molecular modeling protonation state computer aided drug design

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[1]  Gohlke, H.; Klebe, G. Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors. Angew. Chem., Int. Ed., 2002, 41, 2644-2676.
[2]  Bühm, H. J.; Stahl, M. The use of scoring functions in drug discovery applications. In Reviews in Computational Chemistry; Lipkowitz, K. B., Boyd, D. B., Eds.; Wiley-VCH: New York, 2002; Vol. 18, pp 41-87.
[3]  Teague, S. J. Implications of protein flexibility for drug discovery. Nat. Rev. Drug Discovery, 2003, 2, 527-541.
[4]  Perola, E.; Charifson, P. S. Conformational Analysis of Drug-Like Molecules Bound to Proteins: An Extensive Study of Ligand Reorganization upon Binding. J. Med. Chem., 2004, 47, 2499-2510.
[5]  Butler, K. T.; Luque, F. J.; Barril, X. Toward accurate relative energy predictions of the bioactive conformation of drugs. J. Comput. Chem., 2009, 30, 601-610.
[6]  Carlson, H. A.; McCammon, J. A. Accommodating Protein Flexibility in Computational Drug Design. Mol. Pharmacol., 2000, 57, 213-218.
[7]  Jiang, F.; Kim, S. H. Soft Docking - Matching Of Molecular-Surface Cubes. J. Mol. Biol., 1991, 219, 79-102.
[8]  Nakajima, N.; Higo, J.; Kidera, A.; Nakamura, H. Flexible docking of a ligand peptide to a receptor protein by multicanonical molecular dynamics simulation. Chem. Phys. Lett., 1997, 278, 297.
[9]  Wasserman, Z. R.; Hodge, C. N. Fitting an inhibitor into the active site of thermolysin: A molecular dynamics case study. Proteins-Struct. Funct. Genet., 1996, 24, 227
[10]  Dinola, A.; Roccatano, D.; Berendsen, H. J. C. Molecular-Dynamics Simulation Of The Docking Of Substrates To Proteins. Proteins-Struct. Funct. Genet., 1994, 19, 174.
[11]  Sippl, M. J. Calculation of conformational ensembles from potentials of mean force. An approach to the knowledge-based prediction of local structures in globular proteins. J. Mol. Biol., 1990, 213, 859-883.
[12]  Nangia, A.; Desiraju, G. R. Supramolecular structures - Reason and imagination. Acta Cryst. A, 1998, 54, 934-944.
[13]  Nangia, A. Database research in crystal engineering. Cryst Eng Comm., 2002, 17, 93-101.
[14]  Rivas, J. C. M. , Brammer, L. Self-assembly of 1-D chains of different topologies using the hydrogen-bonded inorganic supramolecular synthons N-H···Cl2M or N-H···Cl3M. Inorg. Chem., 1998, 37, 4756-4757.
[15]  Steiner, T. The hydrogen bond in the solid state. Angew. Chem. Int. Ed., 2002, 41, 48-76.
[16]  Steiner, T. Unrolling the hydrogen bond properties of C-HO interactions. Chem. Commun., 1997, 1997, 727-724.
[17]  Jones, P. G.; Ahrens, B. Bis(diphenylphosphino)methane and related ligands as hydrogen bond donors. Chem. Commun. 1998, 1998, 2307-2308.
[18]  Lommerse, J. P. M.; Stone, A. J.; Taylor, R.; Allen, F. H. The nature and geometry of intermolecular interactions between halogens and oxygen or nitrogen. J. Am. Chem. Soc., 1996, 118, 3108-3116.
[19]  Chandrasekhar, V.; Baskar, V.; Kingsley, S.; Nagendran, S.; Butcher, R. J. First characterisation of weak hydrogen bonds in organoantimony compounds: C-H···Cl-Sb-mediated, zig-zag, supramolecular polymeric architecture in [Ph2Sb(Cl){S2C2(CN)2}]. Cryst. Eng. Comm., 2001, 17, 64-66.
[20]  Banerjee, R.; Desiraju, G. R.; Mondal, R.; Howard, J. A. K. Organic chlorine as a hydrogen-bridgeacceptor: Evidence for the existence of intramolecular O-H⋅⋅⋅Cl-C interactions in some gem-alkynols. Chem. Eur. J., 2004, 10, 3373-3383.
[21]  Waters, M. L. Aromatic interactions in model systems. Curr. Opin. Chem. Biol., 2002, 6, 736-741.
[22]  Gilson, M. K.; Zhou, H. X. Calculation of protein-ligand binding affinities. Annu. Rev. Biophys. Biomol. Struct., 2007, 36, 21-42.
[23]  Honig, B.; Sharp, K.; Yang, A. S. Macroscopic models of aqueous solutions: biological and chemical applications. J. Phys. Chem., 1993, 97, 1101-1109.
[24]  Rashin, A. A. Aspects of protein energetics and dynamics. Prog. Biophys. Mol. Biol., 1993, 60, 73-200.
[25]  Moitessier, N.; Englebienne, P.; Lee, D.; Lawandi, J.; Corbeil, C. R. Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go. Br. J. Pharmacol., 2008, 153(Suppl. 1), S7-S26.
[26]  Mancera, R. L. Molecular modeling of hydration in drug design. Curr. Opin. Drug. Discov. Dev., 2007, 10, 275-280.
[27]  Kitchen, D. B.; Decornez, H.; Furr, J. R.; Bajorath, J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat. Rev. Drug. Discov., 2004, 3, 935-949.
[28]  Ross, G. A.; Morris, G.M.; Biggin, P. C. Rapid and accurate prediction and scoring of water molecules in protein binding sites. PLoS ONE, 2012, 7, e32036.
[29]  Majeux, N.; Scarsi, M.; Apostolakis, J.; Ehrhardt, C.; Caisch, A. Exhaustive docking of molecular fragments on protein binding sites with electrostatic solvation. Proteins: Struct., Funct., Genet., 1999, 37, 88-105.
[30]  Zou, X.; Sun, Y.; Kuntz, I. D. Inclusion of solvation in ligand binding free energy calculations using the generalized-Born model. J. Am. Chem. Soc,. 1999, 121, 8033-8043.
[31]  Vorobjev, Y. N. Advances in implicit models of water solvent to compute conformational free energy and molecular dynamics of proteins at constant pH. Adv. Protein Chem. Struct. Biol., 2011, 85, 281-322
[32]  Banba, S.; Guo, Z.; Brooks, C. L. III. New free energy based methods for ligand binding from detailes structure-function to multiple-ligand screening. in Free energy calculations in rational drug design. Reddi, M. R.; Erion, M. D. Eds. Kluwer/Plenum Publishers, New York, 2001, pp195-223.
[33]  Aqvist, J.; Medina, C.; Samuelsson, J. E. A new method for predicting binding affinity in computer-aided drug design. Protein. Eng. Des. Sel., 1994, 7, 385-391.
[34]  Carlson, H. A.; Jorgensen, W. L. An extended linear response method for determining free energies of hydration. J. Phys. Chem., 1995, 99, 10667-10673.
[35]  Chen, J.; Brooks, C. L. III; Khandogin, J. Recent advances in implicit solvent-based methods for biomolecular simulations. Curr. Opin. Struct. Biol., 2008, 18, 140-148.
[36]  Roux, B.; Simonson, T. Implicit solvent models. Biophys. Chem., 1999, 78, 1-20.
[37]  Simonson, T. Macromolecular electrostatics: continuum models and their growing pains. Curr. Opin. Struct. Biol., 2001, 11, 243-252.
[38]  Baker, N. A. Improving implicit solvent simulations: a Poisson-centric view. Curr. Opin. Struct. Biol., 2005, 15, 137-143.
[39]  Nicholls, A.; Mobley, D. L.; Guthrie, J. P.; Chodera, J. D.; Bayly, C. I.; Cooper, M. D.; Pande, V. S. Predicting small-molecule solvation free energies: an informal blind test for computational chemistry. J. Med. Chem., 2008, 51, 769-779.
[40]  Mobley, D. L.; Bayly, C. I.; Cooper, M. D.; Dill, K. A. Predictions of hydration free energies from all-atom molecular dynamics simulations. J. Phys. Chem. B, 2009, 113, 4533-4537.
[41]  Mobley, D. L.; Bayly, C. I.; Cooper, M. D.; Shirts, M. R.; Dill, K. A. Small molecule hydration free energies in explicit solvent: an extensive test of fixed-charge atomistic simulations. J. Chem. Theory. Comput., 2009, 5, 350-358.
[42]  Mobley, D. L.; Dill, K. A.; Chodera, J. D. Treating entropy and conformational changes in implicit solvent simulations of small molecules. J. Phys. Chem. B, 2008, 112, 938-946.
[43]  Nicholls, A.; Wlodek, S.; Grant, J. A. The SAMP1 solvation challenge: further lessons regarding the pitfalls of parametrization. J. Phys. Chem. B, 2009, 113, 4521-4532.
[44]  Li, Z.; Lazaridis, T. Water at biomolecular binding interfaces. Phys. Chem. Chem. Phys., 2007, 9, 573-581.
[45]  de Graaf, C.; Vermeulen, N. P. E.; Feenstra, K. A. Cytochrome P450 in silico: an integrative modeling approach. J. Med. Chem., 2005, 48, 2725-2755.
[46]  Barillari, C.; Taylor, J.; Viner, R.; Essex, J. W. Classification of water molecules in protein binding sites. J. Am. Chem. Soc. 2007, 129, 2577-2587.
[47]  Lu, Y.; Wang, R.; Yang, C. Y.; Wang, S. Analysis of ligand-bound water molecules in high-resolution crystal structures of protein-ligand complexes. J. Chem. Inf. Model. 2007, 47, 668-675.
[48]  Fitzpatrick, P. A.; Steinmetz, A. C. U.; Ringe, D.; Klibanov, A. M. Enzyme crystal structure in a neat organic solvent. Proc. Nat. Acad. Sci. U.S.A. 1993, 90, 8653-8657.
[49]  Raymer, M. L.; Sanschagrin, P. C.; Punch, W. F.; Venkataraman, S.; Goodman, E. D.; Kuhn, L. A. Predicting conserved water-mediated and polar ligand interactions in proteins using a K-nearest-neighbors genetic algorithm. J. Mol. Biol. 1997, 265, 445-464.
[50]  Huang, W. J.; Blinov, N.; Wishart, D. S.; Kovalenko, A. Role of Water in Ligand Binding to Maltose-Binding Protein: Insight from a New Docking Protocol Based on the 3D- Model., 2015, 55, 317-328.
[51]  ten Brink, T.; Exner, T. E. Influence of protonation, tautomeric, and stereoisomeric states on protein-ligand docking results. J. Chem. Inf. Model., 2009, 49, 1535-1546.
[52]  Kastritis, P. L.; Bonvin, A. M. J. J. On the binding affinity of macromolecular interactions: daring to ask why prorteins interact. J. R. Soc. Interface, 2012, 10:20120835.
[53]  Fersht, A. R.; Shi, J-P.; Knill-Jones, J.; Lowe, D. M.; Wilkinson, A. J.; Blow, D. M.; Brick, P.; Carter,P.; Waye, M. M. Y.; Winter, G. Hydrogen bonding and biological specificity analysed by protein engineering. Nature, 1985, 314, 235-238.
[54]  Bostrom, J.; Norrby, P-O.; Liljefors, T. Conformational energy penalties of protein-bound ligands. J. Comput. Aided Mol. Des., 1998 12, 383-396.
[55]  Roy, S.; Bagchi, B. Free energy barriers for escape of water molecules from protein hydration layer. J. Phys. Chem. B, 2012, 116, 2958-2968.
[56]  Ritschel, T.; Philiph, C.; Kohler, P. C.; Neudert, G.; Heine, A.; Diederich, F.; Klebe, G. How to replace the residual solvation shell of polar active site residues to achieve nanomolar inhibition of tRNA-guanine transglycosidase. ChemMedChem, 2009, 4, 2012-2023
[57]  Kadirvelraj R, Foley BL, Dyekjaer JD, Woods RJ (2008) Involvement of water in carbohydrate-protein binding: Concanavalin A revisited. J Am Chem Soc 130, 106933-16942.
[58]  Nguyen, C. N.; Kurtzman Young, T.; Gilson, M. K. Grid inhomogeneus solvation theory: Hydration structure and thermodynamics of the miniature receptor cucurbit[7]uril. J. Chem. Phys., 2012, 137, 44-101.
[59]  Water…where it matters, when it matters. Available: Accesed 2015 May 13.
[60]  A new paradigm in ligand optimization. Available: Accesed 2015 May 13.
[61]  Genheden, S.; Luchko, T.; Kovalenko, A.; Ryde, U. An MM/3D-RISM approach for ligand binding affinities. J. Phys. Chem., 2010, 114, 8505-8516.
[62]  Genheden, S.; Mikulskis, P.; Hu, L.; Kongsted, J.; Söderhjelm, P.; Ryde, U. Accurate predictions of nonnnpolar solvation free energies require explicit consideration of binding-site hydration. J. Am. Chem. Soc., 2011, 133, 13081-13092.
[63]  Ben Naim, A. Solvent effects on protein association and protein folding. Biopolymers, 1990, 29, 567-596.
[64]  Li, Z.; Lazaridis, T. Thermodynamics of buried water clusters at a protein at ligand binding interface. J. Phys. Chem. B, 2006, 110, 1464-1475.
[65]  Li, Z.; Lazaridis, T. The effect of water displacement on binding thermodynamics: concanavalin A. J. Phys. Chem. B, 2005, 109, 662-670.
[66]  Sawada, Y.; Sokabe, M. Molecular dynamics study on protein-water interplay in the mechanogating of the bacterial mechanosensitive channel MscL. Eur. Biophys. J., 2015, 44, 531-543.
[67]  Amram, S; Ganoth, A.; Tichon, O.; Peer, D.; Nachliel, E.; Gutman, M.; Tsfadia, Y. Structural Characterization of the Drug Translocation Path of MRP1/ABCC1. Isr. J. Chem., 2014, 54, 1382-1393.
[68]  Kollman, P. A.; 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. A.; Cheatham, T. E., III. Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models. Acc. Chem. Res., 2000, 33, 889-897.
[69]  Wang, J.; Kang, X.; Kuntz, I. D.; Kollman, P. A. Hierarchical database screenings for HIV-1 reverse transcriptase using a pharmacophore model, rigid docking, solvation docking, and MM-PB/SA. J. Med. Chem., 2005, 48, 2432-2444.
[70]  Sitkoff, D.; Sharp, K. A.; Honig, B. Accurate Calculation of Hydration Free Energies Using Macroscopic Solvent Models. J. Phys. Chem., 1994, 98, 1978-1983.
[71]  Rush, T. S. III; Manas, E. S.; Tawa, G. J.; Alvarez, J. C. in Virtual Screening in Drug Discovery (Alvarez, J.C. and Shoichet, B.K., Eds.), Taylor & Francis, Boca Raton, FL. 2005, pp. 249-277.
[72]  Kroemer, R. T. Structure-based drug design: Docking and scoring. Current Protein and Peptide Science, 2007, 8, 312-328.
[73]  Verdonk, M. L.; Chessari, G.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Nissink, J. W. M.; Taylor, R. D.; Taylor, R. Modeling water molecules in protein-ligand docking using GOLD. J. Med. Chem. 2005, 48, 6504-6515
[74]  García-Sosa, A. T.; Mancera, R. L.; Dean, P. M. WaterScore: a novel method for distinguishing between bound and displaceable water molecules in the crystal structure of the binding site of protein-ligand complexes. J. Mol. Model., 2003, 9, 172-182.
[75]  Goodford, P. J. A. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem., 1985, 28, 849-857.
[76]  Clarke, C.; Woods, R. J.; Gluska, J.; Cooper, A.; Nutley, M. A.; Boons, G.-J. Involvement of water in carbohydrate-protein binding. J. Am. Chem. Soc., 2001, 123, 12238-12247.
[77]  Rarey, M.; Kramer, B. Lengauer, T. The particle concept: placing discrete water molecules during protein-ligand docking predictions. Proteins: Structure, Function, and Bioinformatics, 1999, 34, 17-28.
[78]  Schnecke, V.; Kuhn, L .A. Virtual screening with solvation and ligand-induced complementarity. Perspect. Drug Discov. Des., 2000, 20, 171-190.
[79]  Sousa, S. F.; Fernandes, P. A.; Ramos, M. J. Protein-ligand docking: current status and future challenges. Proteins: Structure, Function, and Bioinformatics, 2006, 65, 15-26.
[80]  Kim, R.; Skolnick, J. Assessment of programs for ligand binding affinity prediction. J. Comput. Chem., 2008, 29, 1316-1331.
[81]  Ni, H.; Sotriffer, C. A.;, McCammon, J. A. Ordered water and ligand mobility in the HIV-1 integrase-5CITEP complex: a molecular dynamics study. J. Med. Chem., 2001, 44, 3043-3047.
[82]  Sarkhel, S.; Desiraju, G. R. N-HO, O-HO, and C-HO hydrogen bonds in protein-ligand complexes: strong and weak interactions in molecular recognition. Proteins: Structure, Function, and Bioinformatics, 2004, 54, 247-259.
[83]  Bohm, H. J. The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known threedimensional structure. J. Comput. Aided Mol. Des., 1994, 8, 243-256.
[84]  Jain, A. N. Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities. J. Comp. Aided Mol. Des., 1996, 10, 427-440.
[85]  Deng, Y.; Roux, B. Computation of binding free energy with molecular dynamics and grand canonical Monte Carlo simulations. J. Chem. Phys., 2008, 128, 115103.
[86]  Young, T.; Abel, R.; Kim, B.; Berne, B. J.; Friesner, R. A. Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding. Proc. Nat. Acad. Sci. USA, 2007, 104, 808-813.
[87]  Roberts, B. C.; Mancera, R. L. Ligand-protein docking with water molecules. J. Chem. Inf. Mod., 2008, 48, 397-408.
[88]  Thilagavathi, R.; Mancera, R. L. Ligand-protein cross-docking with water molecules. J. Chem. Inf. Mod., 2010, 50, 415-421.
[89]  Lie, M. A.; Thomsen, R.; Pedersen, C. N. S.; Schiøtt, B.; Christensen, M.H. Molecular Docking with Ligand Attached Water Molecules. J. Chem. Inf. Model., 2011, 51, 909-917.
[90]  Roe, S. M.; Prodromou, C.; O’Brien, R.; Ladbury, J. E.; Piper, P.W.; Pearl, L. H. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med. Chem., 1999, 42, 260-266.
[91]  Sleigh, S. H.; Seavers, P. R.; Wilkinson, A. J.; Ladbury, J. E.; Tame, J. R. Crystallographic and calorimetric analysis of peptide binding to OppA protein. J. Mol. Biol., 1999, 291, 393-415.
[92]  Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong Y. N. () Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science, 1994, 263, 380-384.
[93]  de Beer, S. B.; Vermeulen, N. P.; Oostenbrink, C. The role of water molecules in computational drug design. Curr. Top. Med. Chem., 2010, 10, 55-66.
[94]  Mancera, R. L. Molecular modelling of hydration in drug design. Curr. Opin. Drug. Discov. Devel., 2007, 10, 275-280.
[95]  Wong, S. E.; Lightstone, F. C. Accounting for water molecules in drug design. Exp. Opin. Drug. Discov., 2011, 6, 65-74.
[96]  Hussain, A.; Melville, J.; Hirst, J. Molecular docking and QSAR of aplyronine A and analogues: potent inhibitors of actin. J. Comput. Aided Mol. Des., 2010, 24, 1-15.
[97]  Pastor, M.; Cruciani, G.; Watson, K. A. A strategy for the incorporation of water molecules present in a ligand binding site into a three-dimensional quantitative structure-activity relationship analysis. J. Med. Chem. 1997, 40, 4089-4102.
[98]  Taha, M. O.; Habash, M.; Al-Hadidi, Z.; Al-Bakri, A.; Younis, K.; Sisan, S. Docking-based comparative intermolecular contacts analysis as new 3-D QSAR concept for validating docking studies and in silico screening: NMT and GP inhibitors as case studies. J. Chem. Inf. Model. 2011, 51, 647-669.
[99]  Wallnoefer, H. G.; Handschuh, S.; Liedl, K. R.; Fox, T. Stabilizing of a globular protein by a highly complex water network: a molecular dynamics simulation study on factor Xa. J. Phys. Chem. B, 2010, 114, 7405-7412.
[100]  Luccarelli, J.; Michel, J.; Tirado-Rives, J.; Jorgensen; W. L. Effects of water placement on predictions of binding affinities for p38a MAP kinase inhibitors. J. Chem. Theory. Comput., 2010, 6, 3850-3856.
[101]  Wallnoefer, H. G.; Liedl, K R.; Fox, T. A challenging system: Free energy prediction for factor Xa. J. Comput. Chem., 2011, 32, 1743-1752.
[102]  de Graaf, C.; Oostenbrink, C; Keizers, P. H.; van der Wijst, T.; Jongejan, A.; Vermeulen, N. P. E. Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking. J. Med. Chem., 2006, 49, 2417-2430.
[103]  de Graaf, C.; Pospisil, P.; Pos, W.; Folkers, G.; Vermeulen, N. P. E. Binding mode prediction of cytochrome P450 and thymidine kinase protein-ligand complexes by consideration of water and rescoring in automated docking. J. Med. Chem., 2005, 48, 2308-2318.
[104]  Santos, R.; Hritz, J.; Oostenbrink, C. Role of water in molecular docking simulations of cytochrome P450 2D6. J. Chem. Inf. Model. 2010, 50, 146-154.
[105]  Bellocchi, D.; Macchiarulo, A.; Constantino, G.; Pellicciar, R. Docking studies on PARP-1 inhibitors: insights into the role of a binding pocket water molecule. Bioorg. Med. Chem. 2005, 13, 1151-1157.
[106]  Chen, J. M.; Xu, S. L; Wawrzak, Z.; Basarab, G. S.; Jordan, D. B. Structure-based design of potent inhibitors of scytalone dehydratase: displacement of a water molecule from the active site. Biochemistry, 1998, 37, 17735-17744.
[107]  Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B. Jr.; Greenberger, L. M.; Gruber, B. C.; Johnson, B. D.; Mamuya, N.; Nilakantan, R.; Reich, M. F.; Shen, R.; Tsou, H-R.; Upeslacis, E.; Wang, Y. F.; Wu, B.; Ye, F.; Zhang, N. 4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors. J. Med. Chem., 2000, 43, 3244-3256.
[108]  Mikol ,V.; Papageorgiou, C.; Borer, X. The role of water molecules in the structure-based design of (5-hydroxynorvaline)-2-cyclosporin: synthesis, biological activity, and crystallographic analysis with cyclophilin A. J. Med. Chem., 1995, 38, 3361-3367.
[109]  Garcia-Sosa, A. T.; Mancera, R. L. Free energy calculations of mutations involving a tightly bound water molecule and ligand substitutions in a ligand-protein complex. Mol. Inf., 2010, 29, 589-600.
[110]  Michel, J.; Tirado-Rives, J.; Jorgensen, W. L. Energetics of displacing water molecules from protein binding sites: Consequences for ligand optimization. J. Am. Chem. Soc., 2009, 131, 15403-15411.
[111]  Lloyd, D. G.; Garcia-Sosa, A. T.; Alberts, I. L.; Todorov, N. P.; Mancera, R. L. The effect of tightly bound water molecules on the structural interpretation of ligand-derived pharmacophore models. J. Comp. Aided. Mol. Des., 2004, 18, 89-100.
[112]  Garcia-Sosa, A. T.; Firth-Clark, S.; Mancera, R. L. Including tightly-bound water molecules in de novo drug design. Exemplification through the in silico generation of poly(ADP-ribose)polymerase ligands. J. Chem. Inf. Model., 2005, 45, 624-633.
[113]  Garcia-Sosa, A. T.; Mancera, R. L. The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors. J. Mol. Mod. 2006, 12, 422-431.
[114]  Mancera, R. L. De novo ligand design with explicit water molecules: An application to bacterial neuraminidase. J. Comput. Aided Mol. Des., 2002, 16, 479-499.
[115]  Carugo, O.; Bordo, D. How many water molecules can be detected by protein crystallography? Acta Crystallogr. D. Biol. Crystallogr., 1999, 55, 479-483.
[116]  Davis, A. M.; Teague, S. J.; Kleywegt, G. J. Application and limitations of X-ray crystallographic data in structure-based ligand and drug design. Angew. Chem., Int. Ed., 2003, 42, 2718-2736.
[117]  Ernst, J. A.; Clubb, R. T.; Zhou, H.-X.; Gronenborn, A. M.; Clore, G. M. Demonstration of positionally disordered water within a protein hydrophobic cavity by NMR. Science, 1995, 267, 1813-1816.
[118]  Huang, N.; Shoichet, B. K. Exploiting ordered waters in molecular docking. J. Med. Chem., 2008, 51, 4862-4865.
[119]  Kellogg, G. E.; Semus, S. F.; Abraham, D. J. HINT: a new method of empirical hydrophobic field calculation for CoMFA. J. Comput. Aided Mol. Des., 1991, 5, 545-552.
[120]  Chen, D. L.; Kellogg, G. E. A computational tool to optimize ligand selectivity between two similar biomacromolecular targets. J. Comput. Aided Mol. Des., 2005, 19, 69-82.
[121]  Amadasi, A.; Spyrakis, F.; Cozzini, P.; Abraham, D. J.; Kellogg, G. E.; Mozzarelli, A. Mapping the energetics of water-protein and water-ligand interactions with the “natural” HINT forcefield: Predictive tools for characterizing the roles of water in biomolecules. J. Mol. Biol. 2006, 358, 289-309.
[122]  Amadasi, A.; Surface, J. A.; Spyrakis, F.; Cozzini, P.; Mozzarelli. A.; Kellogg, G. E. Robust classification of ‘‘relevant’’ water molecules in putative protein binding sites. J. Med. Chem., 2008, 51, 1063-1067.
[123]  Garcia-Sosa, A. T.; Mancera, R. L.; Dean, P. M. WaterScore: a novel method for distinguishing between bound and displaceable water molecules in the crystal structure of the binding site of protein-ligand complexes. J. Mol. Model., 2003, 9, 172-182.
[124]  Trott, O.; Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31, 455-461.
[125]  Purkiss, A.; Skoulakos, S.; Goodfellow, J. M. The protein-solvent interface: a big splash. Philos. Trans. R. Soc. London Ser. A, 2001, 359, 1515-1527.
[126]  Nakasako, M. Large-scale networks of hydration water molecules around bovine beta-trypsin revealed by cryogenic X-ray crystal structure analysis. J. Mol. Biol., 1999, 289, 547-564.
[127]  Higo, J.; Nakasako, M. Hydration structure of human lysozyme investigated by molecular dynamics simulation and cryogenic X-ray crystal structure analyses: On the correlation between crystal water sites, solvent density, and solvent dipole. J. Comput. Chem., 2002, 23, 1323-1336.
[128]  Yokomizo, T.; Higo, J.; Nakasako, M. Patterns and networks of hydrogen-bonds in the hydration structure of human lysozyme. Chem. Phys. Lett., 2005, 410, 31-35.
[129]  Poornima, C. S.; Dean, P. M. Hydration in drug design 1. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions. J. Comput-Aided Mol. Des., 1995, 9, 500-512.
[130]  Hendlich, M.; Bergner, A.; Günter, J.; Klebe, G. Relibase: Design and development of a database for comprehensive analysis of protein-ligand interactions. J. Mol. Biol., 2003, 326, 607-620.
[131]  Poornima, C. S.; Dean, P. M. Hydration in drug design. 2. Influence of local site surface shape on water binding. J. Comput-Aided Mol. Des., 1995, 9, 513-520.
[132]  Chung, E.; Henriques, D.; Renzoni, D.; Zvelebil, M.; Bradshaw, J. M.; Waksman, G.; Robinson, C. V.; Ladbury, J. E. Mass spectrometric and thermodynamic studies reveal the role of water molecules in complexes formed between SH2 domains and tyrosyl phosphopeptides. Struct. Fold. Des., 1998, 6, 1141-1151.
[133]  Baker, E. N.; Hubbard, R. E. Hydrogen bonding in globular proteins. Prog. Biophys. Mol. Biol., 1984, 44, 97-179.
[134]  Sreenivasan, U.; Axelsen, P. H. Buried water in homologous serine proteases. Biochemistry, 1992, 31, 12785-12791.
[135]  Loris, R.; Stas, P. P.; Wyns, L. Conserved waters in legume lectin crystal structures. The importance of bound water for the sequence-structure relationship within the legume lectin family. J. Biol. Chem., 1994, 269, 26722-26733.
[136]  Shaltiel, S.; Cox, S.; Taylor, S. S. Conserved water molecules contribute to the extensive network of interactions at the active site of protein kinase A. Proc. Natl. Acad. Sci., U.S.A. 1998, 95, 484-491.
[137]  Sanschagrin, P. C.; Kuhn, L. A. Cluster analysis of consensus water sites in thrombin and trypsin shows conservation between serine proteases and contributions to ligand specificity. Protein Sci., 1998, 7, 2054-2064.
[138]  Krem, M. M.; Di Cera, E. Conserved water molecules in the specificity pocket of serine proteases and the molecular mechanism of Na+ binding. Proteins: Structure, Function, and Bioinformatics, 1998, 30, 34-42.
[139]  Loris, R.; Langhorst, U.; De Vos, S.; Decanniere, K.; Bouckaert, J.; Maes, D.; Transue, T. R.; Steyaert, J. Conserved water molecules in a large family of microbial ribonucleases. Proteins: Structure, Function, and Bioinformatics, 1999, 36, 117-134.
[140]  Ogata, K.; Wodak, S. J. Conserved water molecules in MHC class-I molecules and their putative structural and functional roles. Protein Eng., 2002, 15, 697-705.
[141]  Bottoms, C. A.; Smith, P. E.; Tanner, J. J. A structurally conserved water molecule in Rossmann dinucleotide-binding domains. Protein Sci., 2002, 11, 2125-2137.
[142]  Prasad, B. V. L. S.; Suguna, K. Role of water molecules in the structure and function of aspartic proteinases. Acta Crystallogr., Sect. D: Biol. Crystallogr., 2002, 58, 250-259.
[143]  Bottoms, C. A.; Schuermann, J. P.; Agah, S.; Henzl, M. T.; Tanner, J. J. Crystal structure of rat R-parvalbumin at 1.05 Å resolution. Protein Sci., 2004, 13, 1724-1734.
[144]  Bottoms, C. A.; White, T. A.; Tanner, J. J. Exploring structurally conserved solvent sites in protein families. Proteins: Structure, Function, and Bioinformatics, 2006, 64, 404-421.
[145]  Zhang, X.-J.; Matthews, B. W. Conservation of solvent-binding sites in 10 crystal forms of T4 lysozyme. Protein Sci., 1994, 3, 1031-1039.
[146]  Carrell, H. L.; Glusker, J. P.; Burger, V.; Manfre, F.; Tritsch, D.; Biellmann, J.-F. X-ray analysis of D-xylose isomerase at 1.9 Å: native enzyme in complex with substrate and with a mechanism-designed inactivator. Proc. Natl. Acad. Sci. U.S.A., 1989, 86, 4440-4444.
[147]  Faerman, C. H.; Karplus, P. A. Consensus preferred hydration sites in six FKBP12-drug complexes. Proteins: Structure, Function, and Bioinformatics, 1995, 23, 1-11.
[148]  Poornima, C. S.; Dean, P. M. Hydration in drug design. 3. Conserved water molecules at the ligand-binding sites of homologous proteins. J. Comput.-Aided Mol. Des., 1995, 9, 521-531.
[149]  Babor, M.; Sobolev, V.; Edelman, M. Conserved positions for ribose recognition: importance of water bridging interactions among ATP, ADP and FAD-protein complexes. J. Mol. Biol., 2002, 323, 523-532.
[150]  Powers, R. A.; Shoichet, B. K. Structure-based approach for binding site idenfication on AmpC beta-lactamase. J. Med. Chem., 2002, 45, 3222-3234.
[151]  Mustata, G.; Briggs, J. M. Cluster analysis of water molecules in alanine racemase and their putative structural role. Protein Eng., 2004, 17, 223-234.
[152]  Boström, J.; Hogner, A.; Schmitt, S. Do structurally similar ligands bind in a similar fashion? J. Med. Chem., 2006, 49, 6716-6725.
[153]  Huang, K.; Lu, W.; Anderson, S.; Laskowski, M.; James, M. N. G. Water molecules participate in proteinase-inhibitor interactions: crystal structure of Leu18, Ala18 and Gly18 variants of turkey ovomucoid inhibitor third domain complexed with Streptomyces griseus proteinase B. Protein Sci., 1995, 4, 1985-1997.
[154]  Engh, R. A.; Brandstetter, H.; Sucher, G.; Eichinger, A.; Baumann, U.; Bode, W.; Huber, R.; Poll, T.; Rudolph, R.; von der Saal, W. Enzyme flexibility, solvent and ‘weak’ interactions characterize thrombin-ligand interactions: Implications for drug design. Structure, 1996, 4, 1353-1362.
[155]  Rejto, P. A.; Verkhivker, G. M. Mean field analysis of FKBP12 complexes with FK506 and rapamycin: Implications for a role of crystallographic water molecules in molecular recognition and specificity. Proteins: Structure, Function, and Bioinformatics, 1997, 28, 313-324.
[156]  Rutenber, E. E.; Stroud, R. M. Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: Assessing specificity and affinity. Structure, 1996, 4, 1314-1324.
[157]  Finley, J. B.; Atigadda, V. R.; Duarte, F.; Zhao, J. J.; Brouillette, M. J.; Air, G. M.; Luo, M. Novel aromatic inhibitors of influenza virus neuraminidase make selective interactions with conserved residues and water molecules in the active site. J. Mol. Biol., 1999, 293, 1107-1119.
[158]  Palomer, A.; Perez, J. J.; Navea, S.; Llorens, O.; Pascual, J.; Garcia, L.; Mauleon, D. Modeling cyclooxygenase inhibition. Implication of active site hydration on the selectivity of ketoprofen analogues. J. Med. Chem., 2000, 43, 2280-2284.
[159]  Vogt, J.; Perozzo, R.; Pautsch, A.; Prota, A.; Schelling, P.; Pilger, B.; Folkers, G.; Scapozza, L.; Schulz, G. E. Nucleoside binding site of Herpes simplex type 1 thymidine kinase analyzed by X-ray crystallography. Proteins: Structure, Function, and Bioinformatics, 2000, 41, 545-553.
[160]  Lemieux, R. U. How water provides the impetus for molecular recognition in aqueous solution. Acc. Chem. Res., 1996, 29, 373-380.
[161]  Wester, M. R.; Johnson, E. F.; Marques-Soares, C.; Dijols, S.; Dansette, P. M.; Mansuy, D.; Stout, C. D. Structure of mammalian cytochrome P4502C5 complexed with diclofenac at 2.1 angstrom resolution: Evidence for an induced fit model of substrate binding. Biochemistry, 2003, 42, 9335-9345.
[162]  Pujadas, G.; Palau, J. Molecular mimicry of substrate oxygen atoms by water molecules in the α-amylase active site. Protein Sci., 2001, 10, 1645-1657.
[163]  Wang, T.; Wade, R. C. Comparative binding energy (COMBINE) analysis of influenza neuraminidase-inhibitor complexes. J. Med. Chem., 2001, 44, 961-971.
[164]  Anstead, G. M; Carlson, K. E.; Katzenellenbogen, J. A. The estradiol pharmacophore: Ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids, 1997, 62, 268-303.
[165]  Grúneberg, S.; Stubbs, M. T.; Klebe, G. Successful virtual screening for novel inhibitors of human carbonic anhydrase: Strategy and experimental confirmation. J. Med. Chem., 2002, 45, 3588-3602.
[166]  Brenk, R.; Naerum, L.; Grädler, U.; Gerber, H.-D.; Garcia, G. A.; Reuter, K.; Stubbs, M. T.; Klebe, G. Virtual screening for submicromolar leads of tRNA-guanine transglycosylase based on a new unexpected binding mode detected by crystal structure analysis. J. Med. Chem., 2003, 46, 1133-1143.
[167]  Pospisil, P.; Kuoni, T.; Scapozza, L.; Folkers, G. Methodology and problems of protein-ligand docking: Case study of dihydroorotate dehydrogenase, thymidine kinase, and phosphodiesterase. 4. J. Recept. Signal Transduct. Res., 2002, 22, 141-154.
[168]  Dunitz, J. D. The entropic cost of bound water in crystals and biomolecules. Science, 1994, 264, 670-671.
[169]  Dunitz, J. D. Win some, lose some: enthalpy-entropy compensation in weak intermolecular interactions. Chem. Biol., 1995, 2, 709-712.
[170]  Ladbury, J. E. Just add water! The effect of water on the specificity of protein-ligand binding sites and its potential application to drug design. Chem. Biol., 1996, 3, 973-980.
[171]  Li, Z.; Lazaridis, T. Thermodynamic contributions of the ordered water molecule in HIV-1 protease. J. Am. Chem. Soc., 2003, 125, 6636-6637.
[172]  Fornabaio, M.; Spyrakis, F.; Mozzarelli, A.; Cozzini, P.; Abraham, D. J.; Kellogg, G. E. Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes. J. Med. Chem., 2004, 47, 4507-4516.
[173]  Cozzini, P.; Fornabaio, M.; Marabotti, A.; Abraham, D. J.; Kellogg, G. E.; Mozzarelli, A. Free energy of ligand binding to protein: Evaluation of the contribution of water molecules by computational methods. Curr. Med. Chem., 2004, 11, 3093-3118.
[174]  Kříž, Z.; Otyepka, M.; Bartová, I.; Koča, J. Analysis of CDK2 active site hydration: A method to design new inhibitors. Proteins: Structure, Function, and Bioinformatics, 2004, 55, 258-274.
[175]  Lu, Y.; Yang, C.-Y.; Wang, S. Binding free energy contributions of interfacial waters in HIV-1 protease/inhibitor complexes. J. Am. Chem. Soc., 2006, 128, 11830-11839.
[176]  Helms, V.; Wade, R. C. Thermodynamics of water mediating protein-ligand interactions in cytochrome P450CAM. A molecular dynamics study. Biophys. J., 1995, 69, 810-824.
[177]  Helms, V.; Wade, R. C. Hydration energy landscape of the active site cavity of cytochrome P450. Proteins: Structure, Function, and Bioinformatics, 1998, 32, 381-396.
[178]  Helms, V.; Wade, R. C. Computational alchemy to calculate absolute protein-ligand binding free energy. J. Am. Chem. Soc., 1998, 120, 2710-2713.
[179]  Hamelberg, D.; McCammon, J. A. Standard free energy of releasing a localized water molecule from the binding pockets of proteins: double-decoupling method. J. Am. Chem. Soc., 2004, 126, 7683-7689.
[180]  Ehrlich, L.; Reczko, M.; Bohr, H.; Wade, R. C. Prediction of protein hydration sites from sequence by modular neural networks. Protein Eng., 1998, 11, 11-19.
[181]  Henchman, R. H.; McCammon, J. A. Extracting hydration sites around proteins from explicit water simulations. J. Comput. Chem., 2002, 23, 861-869.
[182]  Kortveylesi, T.; Dennis, S.; Silberstein, M.; Brown, L.; Vajda, S. Algorithms for computational solvent mapping of proteins. Proteins: Structure, Function, and Bioinformatics, 2003, 51, 340-351.
[183]  Schymkowitz, J. W. H.; Rousseau, F.; Martins, I. C.; Ferkinghoff-Borg, J.; Stricher, F.; Serrano, L. Prediction of water and metal binding sites and their affinities by using the Fold-X force field. Proc. Natl. Acad. Sci. U.S.A., 2005, 102, 10147-10152.
[184]  Carugo, O. Correlation between occupancy and B factor of water molecules in protein crystal structures. Protein Eng., 1999, 12, 1021-1024.
[185]  Carugo, O.; Argos, P. Accessibility to internal cavities and ligand binding sites monitored by protein crystallographic thermal factors. Proteins: Structure, Function, and Bioinformatics, 1998, 31, 201-213.
[186]  Marrone, T. J.; Briggs, J. M.; McCammon, J. A. Structure-based drug design: Computational advances. Annu. ReV. Pharmacol., 1997, 37, 71-90.
[187]  Holdgate, G. A.; Tunnicliffe, A.; Ward, W. H. J.; Weston, S. A.; Rosenbrock, G.; Barth, P. T.; Taylor, I. W. F.; Pauptit, R. A.; Timms, D. The entropic penalty of ordered water accounts for weaker binding of the antibiotic novobiocin to a resistant mutant of DNA gyrase: A thermodynamic and crystallographic study. Biochemistry, 1997, 36, 9663-9673.
[188]  Cherbavaz, D. B.; Lee, M. E.; Stroud, R. M.; Koschl, D. E. Active site water molecules revealed in the 2.1 angstrom resolution structure of a site-directed mutant of isocitrate dehydrogenase. J. Mol. Biol., 2000, 295, 377-385.
[189]  Pickett, S. D.; Sherborne, B. S.; Wilkinson, T.; Bennett, J.; Borkakoti, N.; Broadhurst, M.; Hurst, D.; Kilford, I.; McKinnell, M.; Jones, P. S. Discovery of novel low molecular weight inhibitors of IMPDH via virtual needle screening. Bioorg. Med. Chem. Lett., 2003, 13, 1691-1694.
[190]  García-Sosa, A. T.; Mancera, R. L. The effect of tightly-bound water molecules on scaffold diversity in the computer-aided de novo ligand design of CDK-2 inhibitors. J. Mol. Model., 2006, 12, 422-431.
[191]  Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47, 1739-1749.
[192]  Rao, M. S.; Olson, A. J. Modelling of factor Xa-inhibitor complexes: A computational flexible docking approach. Proteins: Structure, Function, and Bioinformatics, 1999, 34, 173-183.
[193]  Minke, W. E.; Diller, D. J.; Hol, W. G.; Verlinde, C. L. The role of waters in docking strategies with incremental flexibility for carbohydrate derivatives: Heat-labile enterotoxin, a multivalent test case. J. Med. Chem., 1999, 42, 1778-1788.
[194]  Österberg, F.; Morris, G. M.; Sanner, M. F.; Olson, A. J.; Goodsell, D. S. Automated docking to multiple target structures: Incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins: Structure, Function, and Bioinformatics, 2002, 46, 34-40.
[195]  Floriano, W. B.; Vaidehi, N.; Zamanakos, G.; Goddard, W. A., III. HierVLS hierarchical docking protocol for virtual ligand screening of large-molecule databases. J. Med. Chem., 2004, 47, 56-71.
[196]  Nissink, J. W. M.; Murray, C.; Hartshorn, M.; Verdonk, M. L.; Cole, J. C.; Taylor, R. A new test set for validating predictions of protein-ligand interaction. Proteins: Structure, Function, and Bioinformatics, 2002, 49, 457-471.
[197]  Yang, J.-M.; Chen, C.-C. GEMDOCK: A generic evolutionary method for molecular docking. Proteins: Structure, Function, and Bioinformatics, 2004, 55, 288-304.
[198]  de Graaf, C.; Oostenbrink, C.; Keizers, P. H. J.; van der Wijst, T.; Jongejan, A.; Vermeulen, N. P. E. Prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking. J. Med. Chem., 2006, 49, 2417-2430.
[199]  Mendez, R.; Leplae, R.; Lensink, M. F.; Wodak, S. J. Assessment of CAPRI predictions in rounds 3-5 shows progress in docking procedures. Proteins: Structure, Function, and Bioinformatics, 2005 60, 150-169.
[200]  Halperin, I.; Ma, B.; Wolfson, H.; Nussinov, R. Principles of docking: An overview of search algorithms and a guide to scoring functions. Proteins: Structure, Function, and Bioinformatics, 2002, 47, 409-43.
[201]  van Dijk, A. D. J.; Boelens, R.; Bonvin, A. M. J. J. Data-driven docking for the study of biomolecular complexes. FEBS J., 2005, 272, 293-312.
[202]  Chandler, D. Interfaces and the driving force of hydrophobic assembly. Nature, 2005, 437, 640-647.
[203]  van Dijk, A. D. J.; Bonvin, A. M. J. J. Solvated docking: introducing water into the modelling of biomolecular complexes. Bioinformatics, 2006, 22, 2340-2347.
[204]  Raschke,T. M. Water structure and interactions with protein surfaces. Curr. Opin. Struct. Biol., 2006, 16, 152-159.
[205]  Houborg, K.; Harris, P.; Petersen, J.; Rowland, P.; Poulsen, J-C. N.; Schneider, P.; Vind, J.; Larsen, S. Impact of the physical and chemical environment on the molecular structure of Coprinus cinereus peroxidase. Acta Crystallogr. D, 2003, 59, 989-996.
[206]  Yang, J. M.; Chen, C. C. GEMDOCK: A generic evolutionary method for molecular docking. Proteins: Structure, Function, and Bioinformatics, 2004, 55, 288-304.
[207]  Moitessier, N.; Westhof, E.; Hanessian, S. Docking of Aminoglycosides to hydrated and flexible RNA. J. Med. Chem., 2006, 49, 1023-1033.
[208]  Jiang, L.; Kuhlman, B.; Kortemme, T.; Baker, D. A ‘solvated rotainer’ approach to modeling water-mediated hydrogen bonds at protein-protein interfaces. Proteins: Structure, Function, and Bioinformatics, 2005, 58, 893-904.
[209]  Rodier, F.; Bahadur, R. P.; Chakrabarti, P.;l Janin, J. Hydration of protein-protein interfaces. Proteins: Structure, Function, and Bioinformatics, 2005, 60, 36-45.
[210]  Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 1998, 19, 1639−1662.
[211]  Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. A fast flexible docking method using an incremental construction algorithm. J. Mol. Biol., 1996, 261, 470-489.
[212]  Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol., 1997, 267, 727−748.
[213]  Wang, R. X.; Lu, Y. P.; Wang, S. M. Comparative evaluation of 11 scoring functions for molecular docking. J. Med. Chem., 2003, 46, 2287−2303.
[214]  Cummings, M. D.; DesJarlais, R. L.; Gibbs, A. C.; Mohan, V.; Jaeger, E. P. Comparison of automated docking programs as virtual screening tools. J. Med. Chem., 2005, 48, 962−976.
[215]  Kontoyianni, M.; McClellan, L. M.; Sokol, G. S. Evaluation of docking performance: comparative data on docking algorithms. J. Med. Chem., 2004, 47, 558−565.
[216]  Kontoyianni, M.; Sokol, G. S.; McClellan, L. M. Evaluation of library ranking efficacy in virtual screening. J. Comput. Chem., 2005, 26, 11−22.
[217]  Perola, E.; Walters, W. P.; Charifson, P. S. A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance. Proteins: Structure, Function, and Bioinformatics, 2004, 56, 235−249.
[218]  Wang, R. X.; Lu, Y. P.; Fang, X. L.; Wang, S. M. An extensive test of 14 scoring functions using the PDB-bind refined set of 800 protein-ligand complexes. J. Chem. Inf. Comput. Sci., 2004, 44, 2114−2125.
[219]  Bissantz, C.; Folkers, G.; Rognan, D. Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. J. Med. Chem., 2000, 43, 4759−4767.
[220]  Paul, N.; Rognan, D. ConsDock: A new program for the consensus analysis of protein-ligand interactions. Proteins: Structure, Function, and Bioinformatics, 2002, 47, 521−533.
[221]  McConkey, B. J.; Sobolev, V.; Edelman, M. The performance of current methods in ligand-protein docking. Curr. Sci., 2002, 83, 845−856.
[222]  Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. Extra precision Glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein−ligand complexes. J. Med. Chem., 2006, 49, 6177−6196.
[223]  Abel, R.; Young, T.; Farid, R.; Berne, B. J.; Friesner, R. A. Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. J. Am. Chem. Soc., 2008, 130, 2817−2831.
[224]  Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. The particle concept: placing discrete water molecules during protein-ligand docking predictions. Proteins: Structure, Function, and Bioinformatics, 1999, 34, 17−28.
[225]  Liu, J.; He, X.; Zhang, J. Z. H. Improving the Scoring of Protein−Ligand Binding Affinity by Including the Effects of Structural Water and Electronic Polarization. J. Chem. Inf. Model., 2013, 53, 1306−1314.
[226]  Corbeil, C. R.; Therrien, E.; Moitessier, N. Modeling reality for optimal docking of small molecules to biological targets. Curr. Comp. Aided Drug Des., 2009, 5, 241-263.
[227]  B-Rao, C.; Subramanian, J.; Sharma, S. D.. Managing protein flexibility in docking and its applications. Drug Discov. Today, 2009, 14, 394-400.
[228]  Bolstad, E. S.; Anderson, A. C. In pursuit of virtual lead optimization: pruning ensembles of receptor structures for increased efficiency and accuracy during docking. Proteins: Structure, Function, and Bioinformatics, 2009, 75, 62-74.
[229]  Sánchez-Moreno, M.; Gómez-Contreras, F.; Navarro, P.; Marín, C.;Ramírez-Macías, I.; Rosales, M. J.; Campayo, L.; Cano, C.; Sanz, A. M.; Yunta, M. J. R. Imidazole-containing phthalazine derivatives inhibitFe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis. Parasitology, 2015, 142, 1115-1129.
[230]  Sánchez-Moreno,M.; Gómez-Contreras,F.; Navarro, P.; Marín, C.; Olmo, F.; Yunta, M. J. R.; Sanz, A. M.; Rosales, M. J.; Cano, C.; Campayo, L. Phthalazine Derivatives Containing Imidazole Rings Behave as Fe-SOD Inhibitors and Show Remarkable Anti-T. cruzi Activity in Immunodeficient-Mouse Mode of Infection. J. Med. Chem. 2012, 55, 9900−9913
[231]  Rueda, M.; Bottegoni, G.; Abagyan, R. Consistent improvement of cross-docking results using binding site ensembles generated with elastic network normal modes. J. Chem. Inf. Model., 2009, 49, 716-725.
[232]  Kazemi, S.; Kruger, D. M.; Sirockin, F.; Gohlke, H. Elastic potential grids: Accurate and efficient representation of intermolecular interactions for fully flexible docking. ChemMedChem, 2009, 4, 1264-1268.
[233]  Davis, I. W.; Raha, K.; Head, M. S.; Baker, D. Blind docking of pharmaceutically relevant compounds using RosettaLigand. Protein Sci., 2009, 18, 1998-2002.
[234]  Fong, P.; McNamara, J. P.; Hillier, I. H.; Bryce, R. A. Assessment of QM/MM scoring functions for molecular docking to HIV-1 protease. J. Chem. Inf. Model., 2009, 4, 913-924.
[235]  Cincilla, G.; Vidal, D.; Pons, M. An improved scoring function for suboptimal polar ligand complexes. J. Comput. Aided Mol. Des., 2009, 23, 143-152.
[236]  Lang, P. T.; Brozell, S. R.; Mukherjee, S.; Pettersen, E. F.;Meng, E. C.; Thomas, V.; Rizzo, R. C.; Case, D. A.; James, T. L.; Kuntz, I.D. DOCK 6: Combining techniques to model RNA-small molecule complexes. RNA, 2009, 15, 1219-1230.
[237]  Huang, Z.; Wong, C. F. Docking flexible peptide to flexible protein by molecular dynamics using two implicit-solvent models: An evaluation in protein kinase and phosphatase systems. J. Phys. Chem. B, 2009, 113, 14343-14354.
[238]  Villacanas, O.; Madurga, S.; Giralt, E.; Belda, I. Explicit treatment of water molecules in protein-ligand docking. Curr. Comp. Aided Drug Des., 2009, 5, 145-154.
[239]  Englebienne, P.; Moitessier, N. Docking ligands into flexible and solvated macromolecules. 4. Are popular scoring functions accurate for this class of proteins? J. Chem. Inf. Model., 2009, 49, 1568-1580.
[240]  Horbert, R.; Pinchuk, B.; Johannes, E.; Schlosser, J.; Schmidt, D.; Cappel, D.; Totzke, F.; Schächtele, C.; Peifer, C. Optimization of potent DFG-in inhibitors of platelet derived growth factor receptorβ (PDGF-Rβ) guided by water thermodynamics. J. Med. Chem., 2015, 58, 170-182.
[241]  Jacobson, M. P.; Kaminski, G. A.; Friesner, R. A.; Rapp, C. S. Force field validation using protein side chain prediction. J. Phys. Chem. B, 2002, 106, 11673−11680.
[242]  Jacobson, M. P.; Pincus, D. L.; Rapp, C. S.; Day, T. J. F.; Honig, B.; Shaw, D. E.; Friesner, R. A. A hierarchical approach to all-atom protein loop prediction. Proteins: Struct., Funct., Bioinf., 2004, 55, 351−367.
[243]  Kumar, A.; Zhang, K. Y. J. Investigation on the effect of key water molecules in docking performance in CSARdock exercise. J. Chem. Inf. Model., 2013, 53, 1880-1892.
[244]  Yu, B.; Blaber, M.; Gronenborn, A. M.; Clore, G. M.; Caspar, D. L. D. Disordered water within a hydrophobic protein cavity visualized by x-ray crystallography. Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 103−108.
[245]  SZMAP, version; OpenEye Scientific Software, Inc., Santa Fe, NM, USA, 2012; Accessed 2015, May, 21
[246]  Bayden, A. S.; Moustakas, D. T.; Joseph-McCarthy, D.; Lamb, M. L. Evaluating free energies of binding and conservation of crystallographic waters using SZMAP. J. Chem. Inf. Model., 2015, 55, 1552−1565.
[247]  Chen, Z.; Li, Y.; Chen, E.; Hall, D. L.; Darke, P. L.; Culberson, C.; Shafer, J. A.; and Kuo, L. C. Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735, 524, an orally bioavailable inhibitor of the HIV proteases. J. Biol. Chem., 1994, 269, 26344-26348.
[248]  Klein, S. I.; Czekaj, M.; Gardner, C. J.; Guertin, K. R.; Cheney, D. L.; Spada, A. P.; Bolton, S. A.; Brown, K.; Colussi, D.; Heran, C. L.; Morgan, S. R.; Leadley, R. J.; Dunwiddie, C. T.; Perrone, M. H.; Chu, V. Identification and initial structure-activity relationships of a novel class of nonpeptide inhibitors of blood coagulation factor Xa. J. Med. Chem., 1998, 41, 437-450.
[249]  Herron, D. K.; Goodson, T., Jr.; Wiley, M. R.; Weir, L. C.; Kyle, J. A.; Yee, Y. K.; Tebbe, A. L.; Tinsley, J. M.; Mendel, D.; Masters, J. J.; Franciskovich, J. B.; Sawyer, J. S.; Beight, D. W.; Ratz, A. M.; Milot, G.; Hall, S. E.; Klimkowski, V. J.; Wikel, J. H.; Eastwood, B. J.; Towner, R. D.; Gifford-Moore, D. S.; Craft, T. J.; Smith, G. F. 1,2-Dibenzamidobenzene inhibitors of human factor Xa. J. Med. Chem., 2000, 43, 859-872.
[250]  Yee, Y. K.; Tebbe, A. L.; Linebarger, J. H.; Beight, D. W.; Craft, T. J.; Gifford-Moore, D.; Goodson, T., Jr.; Herron, D. K.; Klimkowski, V. J.; Kyle, J. A.; Sawyer, J. S.; Smith, G. F.; Tinsley, J. M.; Towner, R. D.; Weir, L.; Wiley, M. R. N(2)-Aroylanthranilamide inhibitors of human factor Xa. J. Med. Chem., 2000, 43, 873-882.
[251]  Birch, L.; Murray, C. W.; Hartshorn, M. J.; Tickle, I. J.; Verdonk, M. L. Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase. J. Comput.-Aided Mol. Des., 2002, 16, 855-869.
[252]  Pitt, W. R.; Goodfellow, J. M. Modelling of solvent positions around polar groups in proteins. Protein Eng., 1991, 4, 531-537.
[253]  Goodford, P. J. A computational-procedure for determining energetically favorable binding-sites on biologically important macromolecules. J. Med. Chem., 1985, 28, 849-857.
[254]  Miranker, A.; Karplus, M. Functionality maps of binding sites: a multiple copy simultaneous search method. Proteins: Structure, Function, and Bioinformatics, 1991, 11, 29-34.
[255]  Verdonk, M. L.; Cole, J. C.; Taylor, R. SuperStar: A knowledge based approach for identifying interaction sites in proteins. J. Mol. Biol., 1999, 289, 1093-1108.
[256]  Gunther, J.; Bergner, A.; Hendlich, M.; Klebe, G. Utilising structural knowledge in drug design strategies: applications using Relibase. J. Mol. Biol., 2003, 326, 621-636.
[257]  Goodsell, D. S.; Olson, A. J. Automated docking of substrates to proteins by simulated annealing. Proteins: Structure, Function, and Bioinformatics, 1990, 8, 195-202.
[258]  Thilagavathi, R.; Mancera, R. L. Ligand-Protein cross-docking with water molecules. J. Chem. Inf. Model., 2010, 50, 415-421.
[259]  Hatshorn, M. J.; Verdonk, M. L.; Chessari, G.; Brewerton, S. C.; Mooij, W. T. M.; Mortenson, P. N.; Murray, C. W. Diverse, high-quality test set for the validation of protein-ligand docking performance. J. Med. Chem., 2007, 50, 726-741.
[260]  Ball, P. Water as an active constituent in cell biology. Chem. Rev., 2008, 108, 74-108.
[261]  Okada, T.; Fujiyoshi, Y.; Silow, M.; Navarro, J.; Landau, E. M.; Shichida, Y. Functional role of internal water molecules in rhodopsin revealed by X-ray crystallography. Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 5982-5987.
[262]  Levy, Y.; Onuchic, J. N. Water mediation in protein folding and molecular recognition. Annu. Rev. Biophys. Biomol. Struct., 2006, 35, 389-415
[263]  Lemmon, G., Meiler, J. Towards ligand docking including explicit interface water molecules. PLosOne, 2013, 8, e67536.
[264] (accesed 10/15/2015).
[265] (accesed 10/15/2015)
[266]  Weldon DJ, Shah F, Chittiboyina AG, Sheri A, Chada RR, Gut J, Rosenthal PJ, Shivakumar D, Sherman W, Desai P, Jung JC, Avery MA. Synthesis, biological evaluation, hydration site thermodynamics, and chemical reactivity analysis of α-keto substituted peptidomimetics for the inhibition of Plasmodium falciparum. Bioorg Med Chem Letts, 24 (5): 1274-1279, 2014.
[267]  Horbert R, Pinchuk B, Johannes E, Schlosser J, Schmidt D, Cappel D, Totzke F, Schächtele C, and Peifer C. Optimization of Potent DFG-in Inhibitors of Platelet Derived Growth Factor Receptorβ (PDGF-Rβ) Guided by Water Thermodynamics. J Med Chem, 58 (1): 170-182, 2015.
[268]  Pearlstein RA, Sherman W, Abel R. Contributions of water transfer energy to protein-ligand association and dissociation barriers: Watermap analysis of a series of p38α MAP kinase inhibitors. Proteins, 81 (9): 1509-1526, 2013.
[269]  Beuming T, Che Y, Abel R, Kim B, Shanmugasundaram V, Sherman W. Thermodynamic analysis of water molecules at the surface of proteins and applications to binding site prediction and characterization. Proteins, 80: 871-83, 2012.
[270]  Ren, P.; Chun, J.; Thomas, D.G.; Schnieders, M. J.; Marucho, M.; Zhang, J.; Baker, N. A. Biomolecular electrostatics and solvation: a computational perspective. Q. Rev. Biophys., 2012, 45, 427-491.
[271] (accesed 10/19/2015).