Hydrophobicity--shake flasks, protein folding and drug discovery.

Hydrophobic interactions are some of the most important interactions in nature. They are the primary driving force in a number of phenomena. This is mostly an entropic effect and can account for a number of biophysical events such as protein-protein or protein-ligand binding that are of immense importance in drug design. The earliest studies on this phenomenon can be dated back to the end of the 19(th) century when Meyer and Overton independently correlated the hydrophobic nature of gases to their anesthetic potency. Since then, significant progress has been made in this realm of science. This review briefly traces the history of hydrophobicity research along with the theoretical estimation of partition coefficients. Finally, the application of hydrophobicity estimation methods in the field of drug design and protein folding is discussed.

[1]  Glen Eugene Kellogg,et al.  Very empirical treatment of solvation and entropy: a force field derived from Log Po/w , 2001, J. Comput. Aided Mol. Des..

[2]  Pietro Cozzini,et al.  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. , 2004, Journal of medicinal chemistry.

[3]  J. Ponder,et al.  Force fields for protein simulations. , 2003, Advances in protein chemistry.

[4]  A. Leo,et al.  Dependence of hydrophobicity of apolar molecules on their molecular volume. , 1976, Journal of medicinal chemistry.

[5]  R. Cramer,et al.  Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. , 1988, Journal of the American Chemical Society.

[6]  C Silipo,et al.  Calculation of hydrophobic constant (log P) from pi and f constants. , 1975, Journal of medicinal chemistry.

[7]  T Fujita,et al.  Quantitative analyses of hydrophobicity of di- to pentapeptides having un-ionizable side chains with substituent and structural parameters. , 1992, Journal of pharmaceutical sciences.

[8]  L. Molnár,et al.  A neural network based prediction of octanol-water partition coefficients using atomic5 fragmental descriptors. , 2004, Bioorganic & medicinal chemistry letters.

[9]  Glen E. Kellogg,et al.  Hydrophobicity: is LogPo/w more than the sum of its parts? , 2000 .

[10]  A. Leo,et al.  Some advantages of calculating octanol-water partition coefficients. , 1987, Journal of pharmaceutical sciences.

[11]  C. Tanford,et al.  The solubility of amino acids and two glycine peptides in aqueous ethanol and dioxane solutions. Establishment of a hydrophobicity scale. , 1971, The Journal of biological chemistry.

[12]  R. Mannhold,et al.  Calculation of molecular lipophilicity: state of the art and comparison of methods on more than 96000 compounds , 2009, Journal of pharmaceutical sciences.

[13]  Christopher T. Walsh,et al.  Lessons from natural molecules , 2004, Nature.

[14]  A. Leo,et al.  Substituent constants for correlation analysis in chemistry and biology , 1979 .

[15]  Stephen H. White,et al.  Experimentally determined hydrophobicity scale for proteins at membrane interfaces , 1996, Nature Structural Biology.

[16]  E S Huang,et al.  Factors affecting the ability of energy functions to discriminate correct from incorrect folds. , 1997, Journal of molecular biology.

[17]  C. Chothia,et al.  Hydrophobic bonding and accessible surface area in proteins , 1974, Nature.

[18]  B Honig,et al.  Reconciling the magnitude of the microscopic and macroscopic hydrophobic effects. , 1991, Science.

[19]  P. Goodford.  Multivariate characterization of molecules for QSAR analysis , 1996 .

[20]  C. Tanford,et al.  Empirical correlation between hydrophobic free energy and aqueous cavity surface area. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Channa K. Hattotuwagama,et al.  On the hydrophobicity of peptides: Comparing empirical predictions of peptide log P values , 2006, Bioinformation.

[22]  P Buchwald,et al.  Octanol-water partition: searching for predictive models. , 1998, Current medicinal chemistry.

[23]  T Fujita,et al.  Quantitative analyses of the structure-hydrophobicity relationship for N-acetyl di- and tripeptide amides. , 1994, Journal of pharmaceutical sciences.

[24]  J. Butler.  The energy and entropy of hydration of organic compounds , 1937 .

[25]  W Welch,et al.  Structural determinants of high-affinity binding of ryanoids to the vertebrate skeletal muscle ryanodine receptor: a comparative molecular field analysis. , 1994, Biochemistry.

[26]  A. Hopkins,et al.  Navigating chemical space for biology and medicine , 2004, Nature.

[27]  Albert J. Leo,et al.  [25] Hydrophobic parameter: Measurement and calculation , 1991 .

[28]  Robert B. Hermann,et al.  Theory of hydrophobic bonding. II. Correlation of hydrocarbon solubility in water with solvent cavity surface area , 1972 .

[29]  Jouko Yliruusi,et al.  Prediction of physicochemical properties based on neural network modelling. , 2003, Advanced drug delivery reviews.

[30]  M. Letizia Barreca,et al.  Binding models of reversible inhibitors to type-B monoamine oxidase , 2002, J. Comput. Aided Mol. Des..

[31]  I. M. Klotz.  Protein hydration and behavior; many aspects of protein behavior can be interpreted in terms of frozen water of hydration. , 1958, Science.

[32]  A. Carotti,et al.  Comparative molecular field analysis (CoMFA) and docking studies of non-nucleoside HIV-1 RT inhibitors (NNIs). , 1999, Bioorganic & medicinal chemistry.

[33]  Patrick Gaillard,et al.  Molecular Lipophilicity Potential, a tool in 3D QSAR: Method and applications , 1994, J. Comput. Aided Mol. Des..

[34]  A. Ghose,et al.  Atomic Physicochemical Parameters for Three‐Dimensional Structure‐Directed Quantitative Structure‐Activity Relationships I. Partition Coefficients as a Measure of Hydrophobicity , 1986 .

[35]  A. D. McLachlan,et al.  Solvation energy in protein folding and binding , 1986, Nature.

[36]  R. Doolittle,et al.  A simple method for displaying the hydropathic character of a protein. , 1982, Journal of molecular biology.

[37]  Glen Eugene Kellogg,et al.  HINT: A new method of empirical hydrophobic field calculation for CoMFA , 1991, J. Comput. Aided Mol. Des..

[38]  Han van de Waterbeemd,et al.  Substructure and whole molecule approaches for calculating log P , 2001, J. Comput. Aided Mol. Des..

[39]  K. Dill,et al.  A lattice statistical mechanics model of the conformational and sequence spaces of proteins , 1989 .

[40]  T. Keller,et al.  A practical view of 'druggability'. , 2006, Current opinion in chemical biology.

[41]  James W. McFarland,et al.  Parabolic relation between drug potency and hydrophobicity , 1970 .

[42]  M. Fornabaio,et al.  A Second Receptor Binding Site on Human Parainfluenza Virus Type 3 Hemagglutinin-Neuraminidase Contributes to Activation of the FusionMechanism , 2007, Journal of Virology.

[43]  H. Scheraga,et al.  The role of hydrophobic interactions in initiation and propagation of protein folding , 2006, Proceedings of the National Academy of Sciences.

[44]  I. Pajeva,et al.  Molecular modeling of phenothiazines and related drugs as multidrug resistance modifiers: a comparative molecular field analysis study. , 1998, Journal of medicinal chemistry.

[45]  Tudor I. Oprea.  Current trends in lead discovery: Are we looking for the appropriate properties? , 2002, J. Comput. Aided Mol. Des..

[46]  Ajay,et al.  Recognizing molecules with drug-like properties. , 1999, Current opinion in chemical biology.

[47]  M. Teeter,et al.  Water structure of a hydrophobic protein at atomic resolution: Pentagon rings of water molecules in crystals of crambin. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Holger H. Hoos,et al.  An ant colony optimisation algorithm for the 2D and 3D hydrophobic polar protein folding problem , 2005, BMC Bioinformatics.

[49]  A. Leo,et al.  Extension of the fragment method to calculate amino acid zwitterion and side chain partition coefficients , 1987, Proteins.

[50]  Albert J. Leo,et al.  Calculating log P(oct) with no missing fragments; The problem of estimating new interaction parameters , 2000 .

[51]  I. Pajeva,et al.  Molecular modeling of triazine type MDR modulators using CoMFA and CoMSIA approaches , 2002, SAR and QSAR in environmental research.

[52]  A. Hopfinger,et al.  Application of SCAP to drug design. 1. Prediction of octanol-water partition coefficients using solvent-dependent conformational analyses. , 1976, Journal of medicinal chemistry.

[53]  C. Hansch,et al.  Analysis of the structure-activity relationship of the sulfonamide drugs using substituent constants. , 1967, Journal of medicinal chemistry.

[54]  C. Hansch,et al.  p-σ-π Analysis. A Method for the Correlation of Biological Activity and Chemical Structure , 1964 .

[55]  M. Oobatake,et al.  Hydration and heat stability effects on protein unfolding. , 1991, Progress in biophysics and molecular biology.

[56]  H. Bull,et al.  Surface tension of amino acid solutions: a hydrophobicity scale of the amino acid residues. , 1974, Archives of biochemistry and biophysics.

[57]  Hiroshi Nikaido,et al.  Efflux-Mediated Drug Resistance in Bacteria , 2012, Drugs.

[58]  Akio Ogino,et al.  Evaluation of the hydrophobic parameters of the amino acid side chains of peptides and their application in QSAR and conformational studies , 1997 .

[59]  Henry S. Frank,et al.  Free Volume and Entropy in Condensed Systems III. Entropy in Binary Liquid Mixtures; Partial Molal Entropy in Dilute Solutions; Structure and Thermodynamics in Aqueous Electrolytes , 1945 .

[60]  C. Hansch,et al.  Partition coefficients and the structure-activity relationship of the anesthetic gases. , 1975, Journal of medicinal chemistry.

[61]  Lemont B. Kier,et al.  Molecular structure description , 1999 .

[62]  Yuan Zhao,et al.  Computation of Octanol-Water Partition Coefficients by Guiding an Additive Model with Knowledge , 2007, J. Chem. Inf. Model..

[63]  Justin L. MacCallum,et al.  Hydrophobic association of α-helices, steric dewetting, and enthalpic barriers to protein folding , 2007, Proceedings of the National Academy of Sciences.

[64]  Peter D. J. Grootenhuis,et al.  Comparative molecular field analysis and energy interaction studies of thrombin-inhibitor complexes , 1999, J. Comput. Aided Mol. Des..

[65]  Gianpaolo Bravi,et al.  Application of MS-WHIM Descriptors: 3. Prediction of Molecular Properties , 2000 .

[66]  J. Proudfoot,et al.  The evolution of synthetic oral drug properties. , 2005, Bioorganic & medicinal chemistry letters.

[67]  Jianhua Yao,et al.  SVM approach for predicting LogP , 2006, Molecular Diversity.

[68]  H. Kubinyi.  QSAR and 3D QSAR in drug design Part 1: methodology , 1997 .

[69]  G. Kellogg,et al.  Design, synthesis and biological evaluation of novel stilbene-based antitumor agents. , 2009, Bioorganic & medicinal chemistry.

[70]  Pietro Cozzini,et al.  Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 2. Computational titration and pH effects in molecular models of neuraminidase-inhibitor complexes. , 2003, Journal of medicinal chemistry.

[71]  Glen E Kellogg,et al.  A computational model for anthracycline binding to DNA: tuning groove-binding intercalators for specific sequences. , 2004, Journal of medicinal chemistry.

[72]  M. Fornabaio,et al.  New Application Design for a 3D Hydropathic Map-Based Search for Potential Water Molecules Bridging between Protein and Ligand # , 2005 .

[73]  C. Hansch,et al.  Chem-bioinformatics and QSAR: a review of QSAR lacking positive hydrophobic terms. , 2001, Chemical reviews.

[74]  THE CORRELATION OF STEROID PARTITION COEFFICIENTS WITH BINDING AFFINITIES TO THE RAT CYTOPLASMIC ANDROGEN RECEPTOR, RAT ANDROGEN‐BINDING PROTEIN, AND HUMAN TESTOSTERONE ESTRADIOL‐BINDING GLOBULIN , 1982 .

[75]  F. Spyrakis,et al.  The consequences of scoring docked ligand conformations using free energy correlations. , 2007, European journal of medicinal chemistry.

[76]  A. Petrauskas,et al.  ACD/Log P method description , 2000 .

[77]  Opera Ti,et al.  3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III. Interpretation of CoMFA results. , 1994 .

[78]  Tudor I. Oprea,et al.  Is There a Difference between Leads and Drugs? A Historical Perspective , 2001, J. Chem. Inf. Comput. Sci..

[79]  Kanti V. Mardia,et al.  Simulating Virtual Protein Calpha Traces with Applications , 2008, J. Comput. Biol..

[80]  Tomasz Arodz,et al.  Computational methods in developing quantitative structure-activity relationships (QSAR): a review. , 2006, Combinatorial chemistry & high throughput screening.

[81]  A. Ghose,et al.  Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragmental Methods: An Analysis of ALOGP and CLOGP Methods , 1998 .

[82]  T. Fujita,et al.  Hydrophobicity of Di‐ and Tripeptides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters , 1989 .

[83]  Anna Marabotti,et al.  Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 1. Models without explicit constrained water. , 2002, Journal of medicinal chemistry.

[84]  Gordon M. Crippen,et al.  Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions , 1987, J. Chem. Inf. Comput. Sci..

[85]  A. Leo,et al.  Partition coefficients and their uses , 1971 .

[86]  Peter E Wright,et al.  Modeling transient collapsed states of an unfolded protein to provide insights into early folding events , 2008, Proceedings of the National Academy of Sciences.

[87]  R. B. Hermann.  Theory of hydrophobic bonding. III. Method for the calculation of the hydrophobic interaction based on liquid state perturbation theory and a simple liquid model , 1975 .

[88]  C. Lipinski.  Drug-like properties and the causes of poor solubility and poor permeability. , 2000, Journal of pharmacological and toxicological methods.

[89]  Pietro Cozzini,et al.  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. , 2006, Journal of molecular biology.

[90]  Raimund Mannhold,et al.  Substructure versus Whole‐molecule Approaches for Calculating Log P , 2003 .

[91]  K. S. Rogers,et al.  Superdelocalizability and charge density. A correlation with partition coefficients. , 1969, Journal of medicinal chemistry.

[92]  L. Lai,et al.  Calculating partition coefficient by atom-additive method , 2000 .

[93]  K. S. Rogers,et al.  A molecular orbital description of the partitioning of aromatic compounds between polar and nonpolar phases. , 1969, Biochimica et biophysica acta.

[94]  G. Hummer,et al.  HYDROPHOBIC FORCE FIELD AS A MOLECULAR ALTERNATIVE TO SURFACE-AREA MODELS , 1999 .

[95]  Luhua Lai,et al.  Calculating Partition Coefficients of Peptides by the Addition Method , 1999 .

[96]  P Buchwald,et al.  Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size‐based model , 1998, Proteins.

[97]  C. Chothia.  The nature of the accessible and buried surfaces in proteins. , 1976, Journal of molecular biology.

[98]  H. Scheraga,et al.  The contribution of hydrophobic bonds to the thermal stability of protein conformations. , 1962, The Journal of biological chemistry.

[99]  Martyn G. Ford,et al.  Simultaneous prediction of aqueous solubility and octanol/water partition coefficient based on descriptors derived from molecular structure , 2001, J. Comput. Aided Mol. Des..

[100]  A. Berthod,et al.  Determination of liquid-liquid partition coefficients by separation methods. , 2004, Journal of chromatography. A.

[101]  P. Kenny,et al.  Toward prediction of alkane/water partition coefficients. , 2008, Journal of medicinal chemistry.

[102]  J. Israelachvili,et al.  Recent progress in understanding hydrophobic interactions , 2006 .

[103]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[104]  Edgar Jacoby,et al.  Molecular lipophilicity in protein modeling and drug design. , 2007, Current medicinal chemistry.

[105]  George D. Rose,et al.  Prediction of chain turns in globular proteins on a hydrophobic basis , 1978, Nature.

[106]  G E Kellogg,et al.  Computationally accessible method for estimating free energy changes resulting from site‐specific mutations of biomolecules: Systematic model building and structural/hydropathic analysis of deoxy and oxy hemoglobins , 2001, Proteins.

[107]  Gilles Klopman,et al.  Calculation of partition coefficients by the charge density method , 1981 .

[108]  W. Kauzmann.  Some factors in the interpretation of protein denaturation. , 1959, Advances in protein chemistry.

[109]  Rahul Jain,et al.  3D-QSAR study of ring-substituted quinoline class of anti-tuberculosis agents. , 2006, Bioorganic & medicinal chemistry.

[110]  A. Ghose,et al.  Atomic physicochemical parameters for three dimensional structure directed quantitative structure‐activity relationships III: Modeling hydrophobic interactions , 1988 .

[111]  R. M. Muir,et al.  Structure-activity relationship in the auxin activity of mono-substituted phenylacetic acids. , 1967, Plant physiology.

[112]  Bernard Testa,et al.  Lipophilicity in Molecular Modeling , 1996, Pharmaceutical Research.

[113]  A COMFA ANALYSIS OF SELECTED PHYSICAL PROPERTIES OF AMINO ACIDS IN WATER , 1995 .

[114]  Glen Eugene Kellogg,et al.  Web application for studying the free energy of binding and protonation states of protein–ligand complexes based on HINT , 2009, J. Comput. Aided Mol. Des..

[115]  Ján Manuch,et al.  Structure-Approximating Inverse Protein Folding Problem in the 2D HP Model , 2005, J. Comput. Biol..

[116]  R. B. Hermann.  Theory of hydrophobic bonding. I. Solubility of hydrocarbons in water, within the context of the significant structure theory of liquids , 1971 .

[117]  Pietro Cozzini,et al.  Robust classification of "relevant" water molecules in putative protein binding sites. , 2008, Journal of medicinal chemistry.

[118]  H. Kubinyi.  QSAR and 3D QSAR in drug design Part 2: applications and problems , 1997 .

[119]  N. Nikolova,et al.  International Union of Pure and Applied Chemistry, LUMO energy ± The Lowest Unoccupied Molecular Orbital (LUMO) , 2022 .

[120]  M J Sippl,et al.  Structure-derived hydrophobic potential. Hydrophobic potential derived from X-ray structures of globular proteins is able to identify native folds. , 1992, Journal of molecular biology.

[121]  C. Cramer,et al.  An SCF Solvation Model for the Hydrophobic Effect and Absolute Free Energies of Aqueous Solvation , 1992, Science.

[122]  D. Winkler,et al.  Investigation of 5-HT4 agonist activities using molecular field analysis , 1998 .

[123]  Luhua Lai,et al.  A New Atom-Additive Method for Calculating Partition Coefficients , 1997, J. Chem. Inf. Comput. Sci..

[124]  I. Muegge.  Selection criteria for drug‐like compounds , 2003, Medicinal research reviews.

[125]  L. Kier.  A theory of inhaled anesthetic action by disruption of ligand diffusion chreodes. , 2003, AANA journal.

[126]  C. Deber,et al.  Erratum: A measure of helical propensity for amino acids in membrane environments , 1994, Nature Structural Biology.

[127]  Glen Eugene Kellogg,et al.  The effect of physical organic properties on hydrophobic fields , 1994, J. Comput. Aided Mol. Des..

[128]  Hydrophobicity of N‐Acetyl‐Di‐ and Tripeptide Amides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters , 1990 .

[129]  C. Hansch,et al.  The parabolic dependence of drug action upon lipophilic character as revealed by a study of hypnotics. , 1968, Journal of medicinal chemistry.

[130]  H. Nar,et al.  Repaglinide and related hypoglycemic benzoic acid derivatives. , 1998, Journal of medicinal chemistry.

[131]  Quantitative Structure-Activity Studies. I. Parameters relating to Hydrophobicity , 1975 .

[132]  M. Fornabaio,et al.  Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity. , 2008, Bioorganic & medicinal chemistry.

[133]  R. M. Muir,et al.  Correlation of Biological Activity of Phenoxyacetic Acids with Hammett Substituent Constants and Partition Coefficients , 1962, Nature.

[134]  C. Lipinski.  Lead- and drug-like compounds: the rule-of-five revolution. , 2004, Drug discovery today. Technologies.

[135]  D. Livingstone.  Theoretical property predictions. , 2003, Current topics in medicinal chemistry.

[136]  Asim Kumar Debnath,et al.  Application of 3D-QSAR techniques in anti-HIV-1 drug design--an overview. , 2005, Current pharmaceutical design.

[137]  K. Meyer.  Contributions to the theory of narcosis , 1937 .