Hydrophobicity fields

HINT adjunct to CoMEA, computes hydrophobic fields EduSoft, Inc. (KeHog/Abraham)... 

The stereoelectronic features produce actions at a distance by the agency of the recognition forces they create. These forces are the hydrophobic effect, and the capacity to enter ionic bonds, van der Waals interactions and H-bonding interactions. The most convenient and informative assessment of such recognition forces is afforded by computahon in the form of MIFs, e.g. lipophilicity fields, hydrophobicity fields, molecular electrostatic potentials (MEPs) and H-bonding fields (see Chapter 6) [7-10]. 

D. J. HINT a new method of empirical hydrophobic field calculation for CoMFA J. Comput.-Aided Mol. Des. 1991, 5, 454—552. 

Fig. 4 (a) The structure of bovine spleen procathepsin B [47] is shown with the active site Cys, Asn and His residues. The PDB coordinates 1QDQ for bovine cath B were obtained from the Structure Database, NCBI. (b) Docking geometry of RAPTA-pentaOH to cat B illustrating the main interactions of the ligand with the residues flanking the active site (reproduced, with modifications, from ref. [28]. The contour map for the hydrophobic field calculated with the sidemap module implemented in Maestro is also shown (transparent). 

Such shifts of pK values are considered in terms of the following causes. A coulombic field which is formed by charged moieties on the polymer, polarizes the catalytic moiety and changes its proton affinity. The pK value of the nucleophile would increase in an anionic field and decrease in a cationic field. The ionization of the nucleophile is promoted by base. The hydrogen bond formation in the nucleophile influences its pK value directly as the charge relay system. A hydrophobic field... 

Generally, hem is readily oxidized by oxygen in an aqueous solution. The hydrophobic reaction in vivo takes place in a hydrophobic field which is formed by apo-enzyme. A stable hydrophobic field disrupts a solvation and makes the hemin stabilize. Poly(phenylalanine)-hemin shows higher catalytic activity than hemin in the oxidation of phenylenediamine (132). This is explained by the fact that the hydrophobic environment fomred by polypeptide plays a significant role in the stabilization of the hemin. 

Moreover, a final 3D-QSAR model vahdation was done using a prospective study with an external test set. The 82 compounds from the data set were used in a lead optimization project. A CoMFA model gave an (cross validated) value of 0.698 for four relevant PLS components and a conventional of 0.938 were obtained for those 82 compounds. The steric descriptors contributed 54% to the total variance, whereas the electrostatic field explained 46%. The CoMSIA model led to an (cross vahdated) value of 0.660 for five PLS components and a conventional of 0.933. The contributions for steric, electrostatic, and hydrophobic fields were 25, 44, and 31%. As a result, it was proved that the basic S4-directed substituents should be replaced against more hydrophobic building blocks to improve pharmacokinetic properties. The structural and chemical interpretation of CoMFA and CoMSIA contour maps directly pointed to those regions in the Factor Xa binding site, where steric, electronic, or hydrophobic effects play a dominant role in ligand-receptor interactions. 

From the studies above, it was shown that the use of 3D-QSAR models led to the identification of binding site regions, where steric, electronic, or hydrophobic effects played a dominant role. Although cationic interactions in both SI and S4 subsites were favorable for in vitro affinity, they might be detrimental for oral bio availability. Thus, the CoMFA steric field contribution could be seen as a balance between pure steric plus hydrophobic effects. The contributions for steric, electrostatic and hydrophobic fields from the CoM-SIA studies were 25, 44, and 31%, respectively. 

In addition to the steric and electrostatic descriptors, it was proposed to use other 3D molecular fields characterized by the sampling over the rectangular grid - in particular, the hydrophobic field/molecular lipophilic potential (MLP), ° hydrogen bonding and quantum-chemical parameters, e.g., orbital densities.Descriptor selection techniques are often recommended to enhance the stability, predictivity and interpretability of the CoMFA models. ... 

In situations where, either from previous QSAR work or from experimental evidence, it is known or suspected that differences in the reactivity of a set of molecules are attributed primarily to their hydrophobic rather than their electrostatic properties it is probably of more use to compare molecular surfaces that display hydrophobicity or polarity information. Indeed, dotted molecular surfaces color-coded by hydrophobic character have been used very successfully by Hansch and coworkers to rationalize QSARs from several different systems (418,419). This concept has been extended to calculate the hydrophobic field surrounding a molecule by Kellogg and Abraham (420,421 )and utilized in CoMFA studies. 

Hydrophatic INTeractions Kellogg and Abraham interaction field -> molecular interaction fields (O hydrophobic fields)... 

HINT), is a hydrophobic field calculated by -> Leo-Hansch hydrophobic fragmental constants scaled by surface area and a distance-dependent function [Kellogg et al., 1991 Kellogg and Abraham, 1992a Abraham and Kellogg, 1993]. Hydropathy is a term used in structural molecular biology to represent the hydrophobicity of amino acid side chains. 

Abraham, D.J. and Kellogg, G.E. (1993). Hydrophobic Fields. In 3D QSAR in Drug Design. Theory, Methods and Applications. (Kubinyi, H., ed.), ESCOM, Leiden (The Netherlands), pp. 506-520. 

A comparative molecular analysis study based on three-dimensional quantum structure-activity relationships was performed by Pajeva and Wiese [159] on 40 phenothiazines and structurally related drugs to predict their MDR modification. More than 350 theoretical models were derived and evaluated using steric, electrostatic and hydrophobic fields alone and in combination. All examined fields were found to contribute to MDR reversing activity, and their hydrophobic fields improved the correlative and predictive power of the models in all cases. The results point out the role of hydropho-bicity as a space-directed molecular property to explain the differences in anti-MDR activity of the drugs under study. 

This space-directed property of lipophilicity was first demonstrated by Pajeva and Wiese both for a series of phenothiazines and thioxanthenes [20] and for a subset of our propafenone-based library [21]. Addition of HI NT-derived hydrophobic fields to... 

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