Lipophilicity fields

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]. 

The major hurdle to overcome in the development of 3D-QSAR models using steric, electrostatic, or lipophilic fields is related to both conformation selection and subsequent suitable overlay (alignment) of compounds. Therefore, it is of some interest to provide a conformation-ally sensitive lipophilicity descriptor that is alignment-independent. In this chapter we describe the derivation and parametrization of a new descriptor called 3D-LogP and demonstrate both its conformational sensitivity and its effectiveness in QSAR analysis. The 3D-LogP descriptor provides such a representation in the form of a rapidly computable description of the local lipophilicity at points on a user-defined molecular surface. 

Hydrophobic GRID uses a probe called DRY to generate 3D lipophilic fields. In... 

In this chapter only QSAR methods which use physicochemical or structural features of molecules will be discussed, while in Chapter 25 3D-QSAR approaches will be presented. These so-called 3D-QSAR techniques, e.g. CoMFA, use the basic statistical principles, such as partial least squares (PLS), of QSAR methods, but in addition use the three-dimensional characteristics of a molecule specifically related to electronic, steric and lipophilic field effects. In these methods the molecular superposition believed relevant to binding to the target is crucial. 

In contrast to finite dimensional vectors, continuous functions play a somewhat different role in MSA as they usually provide an approximate representation of the fields associated with molecules. These include electron density, molecular electrostatic potential, and lipophilicity fields. Although the latter is not a true field... 

D methods consider molecules as objects in space and compute molecular lipophilicity fields. 

D methods combine conformational computations and molecular lipophilicity fields, allowing the assessment of the lipophilicity behavior of solutes in four dimensions. 

In 3D-QSAR, the introduction of a lipophilicity field is required to model specific interactions with a receptor not taken into account by steric and electrostatic fields. The first published examples largely neglect the complex nature of lipophilicity (Figure 1). The compounds in the series used were poorly selected in terms of the variability of their strucmral properties (i.e., steric, electrostatic, or lipophilic). This selection renders the quality of the results largely dependent on possible correlations between the three fields and does not allow one to derive significant conclusions on the importance of a lipophilicity field in CoMFA. However, our recently published examples... 

Computed Lipophilicity Fields An Enhancement of Three-Dimensional Quantitative Structure-Activity Relationships... 

The HINT software is available from Haney Associates, 12010 Medoc Lane, San Diego, CA 92131, as a tool interfaced with the SYBYL package. http //www.i2020.net/edusoft/haney/haney.html The use of the molecular lipophilicity potential to predict virtual log P and to add a lipophilicity field to the CoMFA method can be performed by using the CLIP software available from the Institute of Medicinal Chemistry, University of Lausanne, BEP, CH-1015 Lausanne, Switzerland. http //www.unil.ch/pharm/clip/... 

The CoMSIA analysis using steric, electrostatic, and lipophilic fields as descriptors gave a model with (f of 0.873 and of 0.954. The CoMSIA steric, electrostatic, and lipophilic fields explained the variance of 8.8, 40.9 and 50.2 %, respectively. This indicated that the hydrophobic interaction was a major factor to explain the field properties of the alkylphosphonates lo. Further attempts to combine the hydrogen bond fields with the standard steric, electrostatic, and lipophilic fields did not lead to any significant improvement = 0.869, = 0.952). Indeed,... 

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