Lipophilicity force field profile: An expressive visualization of the lipophilicity molecular potential gradient

Croizet, F.; Langlois, Michel; Dubost, Jean‐Pierre; Braquet, P.; Audry, E.; Dallet, P.; Colleter, J. C.

doi:10.1016/0263-7855(90)80056-l

Cited by 39 publications

(9 citation statements)

References 2 publications

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“…However, it has been demonstrated [15,21,22,25,26] that the hydrophobicity of a molecule can be sufficiently described (at least in a qualitative manner) within empirical concepts based on partition coefficients measured in an octanol/water system. We have demonstrated in the present paper that a Fermi type distance function in so-called lipophilicity potentials (MLP) can be used to map weighted increment values f~ for Crippen's log P data onto the molecular surfaces in a straightforward way.…”

Section: Discussionmentioning

confidence: 99%

“…a large number of atoms contributing to an MLP value at a certain point of the molecular surface may be dominantly determined by a large number of contributions which are far away from this point. Despite the lack of any physical basis for this type of distance dependency of the MLP, useful results could be obtained from the application of this function for visualization of molecular lipophilicity [21,22] for sufficiently small molecules (where the number of contributions is small). Furet et al [21] were able to display MLP profiles on the van der Waals surface of the 20 proteinogenic amino acids using Crippen's single atom fragment lipophilicities.…”

Section: The Molecular Lipophilicity Potentialmentioning

confidence: 99%

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A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces

Heiden

Moeckel

Brickmann

1993

J Computer-Aided Mol Des

183

144

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A new method for display and analysis of lipophilic/hydrophilic properties on molecular surfaces is presented. The present approach is based on the concept of Crippen and coworkers that the overall hydrophobicity of a molecule (measured as the logarithm of the partition coefficient in an octanol/water system) can be obtained as a superposition of single atom contributions. It is also based on the concept of molecular lipophilicity potentials (MLP) first introduced by Audry and coworkers in order to establish a 3D lipophilicity potential profile in the molecular environment. Instead of using a l/r- or an exponential distance law between the atomic coordinates and a point on the molecular surface, a new distance dependency is introduced for the calculation of an MLP-value on the solvent-accessible surface of the molecule. In the present formalism the Crippen values (introduced for atoms in their characteristic structural environment) are 'projected' onto the van der Waals surface of the molecule by a special weighting procedure. This guarantees that only those atomic fragments contribute significantly to the surface values that are in the close neighbourhood of the surface point. This procedure not only works for small molecules but also allows the characterization of the surfaces of biological macromolecules by means of local lipophilicity. Lipophilic and hydrophilic domains can be recognized by visual inspection of computer-generated images or by computational procedures using fuzzy logic strategies. Local hydrophobicities on different molecular surfaces can be quantitatively compared on the basis of the present approach.

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Section: Discussionmentioning

confidence: 99%

Section: The Molecular Lipophilicity Potentialmentioning

confidence: 99%

A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces

Heiden

Moeckel

Brickmann

1993

J Computer-Aided Mol Des

183

144

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“…Hydrophobic similarity has for a long time been considered exclusively on the basis of the well-known n hydrophobicity parameters of Hansch (1971 Croizet et al (1990) extend this concept in order to allow comparisons in three dimensions. As in case of hydrophobic complementarity, the MEF map may also provide a useful means for considering similarity.…”

Section: Similaritymentioning

confidence: 99%

Analysis of molecular recognition: Steric electrostatic and hydrophobic complementarity

Náray‐Szabó

1993

J of Molecular Recognition

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We discuss three important aspects of molecular recognition: steric, electrostatic and hydrophobic. Steric fit means that interacting atoms may not approach each other beyond their van der Waals radii and, simultaneously, crevices should be filled as densely as possible. Electrostatic fit requires the maximum ionic and polar (hydrogen bond or other) interaction between host and guest atoms while the hydrophobic fit corresponds to the association trend between apolar groups in an aqueous medium. Space-filling models, obtained by molecular graphics, illustrate steric complementarity while we use molecular electrostatic potentials (MEPs) and fields (MEFs) to investigate electrostatic and hydrophobic matching. Molecular regions with negative and positive MEPs attract and repel a positive probe charge, respectively, so we consider them as attracting each other. Furthermore we postulate that regions with MEFs of similar magnitude tend to associate more strongly than those with very different fields (similis simili gaudet principle). We apply the above rules to the study of complementarity in the trypsin-BPTI complex and in a crystalline association between styrene epoxide as guest and a camphor-based anthracene derivative as host. We discuss molecular similarity on the same footing as complementarity and give some examples on the application of the concept to the rationalization of relative strengths of trypsin inhibitors.

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“…LPs are qualitative constructs useful for describing and visualizing surface solvation propensities. [38][39][40] They allow lipophilic and hydrophilic regions to be clearly discerned and provide another avenue for comparing the binding sites. Surface LPs of the different GST binding site surfaces are depicted in Figure 5, where a color spectrum ranging from red to yellow to cyan to blue corresponds to a LP gradient ranging from highly liphophilic ( 0.3) to highly hydrophilic (,20.3).…”

Section: Gst Binding Sitesmentioning

confidence: 99%

Ligand-based protein alignment and isozyme specificity of glutathioneS-transferase inhibitors

et al. 1997

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Glutathione S-transferases (GST, E.C.2.5.1.18) comprise a family of detoxification enzymes. Elevated levels of specific GST isozymes in tumor cells are thought responsible for resistance to chemotherapeutics, which renders selective GST inhibitors potentially useful pharmaceutical agents. We discuss the development of a structure activity model that rationalizes the isozyme selectivity observed in a series of 12 glutathione (GSH) analogues. Enzymatic activity data was determined for human P1-1, A1-1, and M2-2 isozymes, and these data were then considered in light of structural features of these three GST proteins. A survey of all GST structures in the PDB revealed that GSH binds to these proteins in a single "bioactive" conformation. To focus on differences between binding sites, we exploited our finding of a common GSH conformation and aligned the GST x-ray structures using bound ligands rather than the backbones of the different proteins. Once aligned, binding site lipophilicity and electrostatic potentials were computed, visualized, and compared. Docking and energy minimization exercises provided additional refinements to a model of selectivity developed initially by visual analysis. Our results suggest that binding site shape and lipophilic character are key determinants of GST isozyme selectivity for close GSH analogues.

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Lipophilicity force field profile: An expressive visualization of the lipophilicity molecular potential gradient

Cited by 39 publications

References 2 publications

A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces

A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces

Analysis of molecular recognition: Steric electrostatic and hydrophobic complementarity

Ligand-based protein alignment and isozyme specificity of glutathioneS-transferase inhibitors

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