Hydrophobic CoMFA

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

The classical CoMFA procedure relies on sterical and electrostatic fields or on spatial interaction energy maps of the potential ligands with standardized hydrophobic or polar probe molecules [56]. In this work, the modified ComPharm approach described in detail elsewhere [25] will be used. Its key differences with respect to classical CoMFA are the following ... 

HINT adjunct to CoMFA, computes hydrophobic fields EduSoft, Inc. (Kellog/Abraham)... 

Finally, the use of a u-polarity field instead of different and more empirical electrostatic, hydrophobic, and hydrogen-bonding fields should lead to considerable advantages in molecular field analysis (MFA) techniques such as ComFA. On the one hand, a includes all three aspects of interactions in a single field, and on the other hand, this interaction picture meanwhile is much better validated quantitatively than the empirical fields presently used in MFA. The only problem here is that a is a surface property and thus less a field in space. With some effort it should be possible to develop reasonable functions for the extension of a perpendicular to the molecular surface and thus to generate a kind of 3D a-filed as required for MFA. 

Molecules are characterized by potential hydrogen bonding, polar, hydrophobic, and electrostatic interactions in 3D space, using 3D molecular fields. Techniques such as Comparative Molecular Field Analysis (CoMFA), which considers the 3D distribution of electrostatic and steric fields, have been applied to congeneric series of enzyme substrates or inhibitors generating 3D QSAR equations. Most examples of such applications are to modeling CYP substrate and inhibitor specificity and these have been extensively reviewed in the literature (Ekins et al., 2000 2001 Ter Laak and Vermeulen, 2001 Ter Laak et al., 2002). 

The next step was made by Klebe et al. [50]. Two 3D-QSAR methods were applied to get three-dimensional quantitative structure-activity relationships using a training set of 72 inhibitors of the benzamidine type with respect to their binding affinities toward Factor Xa to yield statistically reliable models of good predictive power [51-54] the widely used CoMFA method (for steric and electrostatic properties) and the comparative molecular similarity index analysis (CoMSlA) method (for steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor properties). These methods allowed the consideration of various physicochemical properties, and the resulting contribution maps could be intuitively interpreted. 

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. 

On the basis of this equation Zou et al. have concluded that hydrophobic compounds with inductively electron-donating ortho substituents would be favorable for the activity [193]. In continuation of this, Zou and coworkers have carried out CoMFA-based 3D-QSAR analysis of these compounds together with 5-[l-aryl-l,4-dihydro-6-methylpyridazin-4-one-3-ylj-2-arylamino- 1,3,4-oxadiazoles [ 194]. Here also the antifungal activity of these compounds has been found to be well explained by their steric and electrostatic properties. In addition to this, it has confirmed the bioisosterism... 

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. ... 

Tel. 619-566-1127, fax 619-586-1481, e-mail haney netcom.com Hydropathic INTeraction by empirical calculation of atomistic hydrophobicity of molecules. Grid points based on energetics of hydrophobic and hydrophilic fields can be used for contouring a hydrophobic space and for scoring ligand-macromolecule and macromolecule-macromolecule interactions. Interfaced to SYBYL (CoMFA), Insight II, and Chem-X. Silicon Graphics and Evans 8c Sutherland ESV workstations. 

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. 

---