Theoretical Derivation of Heuristic Molecular Lipophilicity Potential: A Quantum Chemical Description for Molecular Solvation (original) (raw)
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Heuristic lipophilicity potential for computer-aided rational drug design
Journal of computer-aided molecular design, 1997
In this contribution we suggest a heuristic molecular lipophilicity potential (HMLP), which is a structure-based technique requiring no empirical indices of atomic lipophilicity. The input data used in this approach are molecular geometries and molecular surfaces. The HMLP is a modified electrostatic potential, combined with the averaged influences from the molecular environment. Quantum mechanics is used to calculate the electron density function rho(r) and the electrostatic potential V(r), and from this information a lipophilicity potential L(r) is generated. The HMLP is a unified lipophilicity and hydrophilicity potential. The interactions of dipole and multipole moments, hydrogen bonds, and charged atoms in a molecule are included in the hydrophilic interactions in this model. The HMLP is used to study hydrogen bonds and water-octanol partition coefficients in several examples. The calculated results show that the HMLP gives qualitatively and quantitatively correct, as well as c...
2000
Methods for the calculation of two properties of interest in drug design, namely free energy of aqueous solvation and lipophilicity (log P), using fragmental methods are reviewed here. Though aqueous solvation free energies are commonly estimated using 'whole molecule' methods such as GB/SA and AMSOL, we have recently shown that fragmental approaches can offer high quality predictions as well (for molecules of the size of 20 atoms or less). In the case of log P predictions, the more commonly used ALOGP and CLOGP approaches represent the two extremes of the fragmental constant approach: ALOGP uses atom-sized fragments and no correction factors; CLOGP uses larger fragments and correction factors, which are typically obtained for each series of molecules separately. A new approach (HLOGP) that uses both smaller (atom-sized) and larger fragments is shown to offer better performance than the other two widely used methods for the prediction of lipophilicity. In this approach, an automated 'inventory' of fragments (bonded atom combinations) within a molecule, known as molecular hologram, is used as a composite descriptor and it is used in conjunction with partial least squares for the prediction of aqueous solvation or lipophilicity. It is emphasized that these different methods are useful in different types of drug design applications involving small organic molecules.
Modeling lipophilicity from the distribution of electrostatic potential on a molecular surface
Journal of Computer-Aided Molecular Design, 1996
Molecular lipophilicity L is represented as a function of four surface electrostatic potential descriptors: L = f(B~,B?,B~,BR). Each B descriptor is computed from the products of elements of molecular surface area, As~, and the molecular electrostatic potential (MEP), V(ri), at the center of an area element: B = ~ Asi V(ri). Octanol water partition coefficients (Pow) are correlated with these four surface-MEP descriptors: log Pow = Co + c~B~+ c2B~+ %B~+ c4BR. Good correlations are obtained for homologous series of aliphatic alcohols, amines and acids, as well as for a set of aromatic compounds with various functional groups. Within this approach, we find that the molecular fragment contributions of surface MEP descriptors to log P are approximately additive. We have computed the values for the following fragments:-CH2- ,-CH3,-COOH,-OH and-NH2. These contributions can be used to estimate the molecular lipophilicity and partition coefficients of new compounds, without additional quantum-mechanical calculations. The proposed approach provides a reasonably accurate tool that can be useful in quantitative structure-activity relations for computer-aided rational drug design. More importantly, the correlation model is conceptually simpler than previous work in the literature and can be improved systematically.
Theoretical Prediction of Lipophilicity for Some Drugs Compounds
Oriental Journal of Chemistry
The theoretical calculations were evaluated for thirty four drug compounds. Many parameters have been calculated theoretically and enter as a model to predicting the best values of practical (Log P). All these compounds were evaluated by semi-empirical (AM1) and Hartree Fock in basis set (HF/STO-3G) using Gaussian 03w. The thermodynamic descriptors like HOMO, LUMO, total energy, Gibbs Free Energy etc were computed and played an important role for predictions the practical lipophilicity values. A linearity was shown when correlated with experimental data. Multiple linear regression analysis was performed to derive quantitative structure activity relationship models which were further evaluated for the predictions.
Journal of Computational Chemistry, 2006
The quantum chemical and structure-based technique heuristic molecular lipophilicity potential (HMLP) is used in the liver alcohol dehydrogenase (LADH) study of molecular family pyrazole and derivatives. The molecular lipophilic index L M , molecular hydrophilic index H M , lipophilic indices l s s, and hydrophilic indices h s s of the substitutes (fragments), and atomic lipophilicity indices l a s are constructed and used in QSAR study. The HMLP indices are correlated with bioactivities of 18 pyrazole derivatives according to the 2D QSAR procedure. The multiple linear regression equation between the bioactivities of pyrazole derivatives and HMLP indices are built using partial least square (PLS) with the optimal statistical quantity (r ϭ 0.987, s ϭ 0.479, F ϭ 47.19). The inhibition mechanism of LADH of the pyrazole derivatives is explained according to the physical meaning of HMLP indices. During the HMLP calculations for the 2D QSAR, the only input parameters are the atomic van der Waals radius without the need to resort to any empirical parameters. Accordingly, HMLP can provide a rigorous theoretical approach with a crystal clear physical meaning for the 2D QSAR.
Solvation Parameters. 2. A Simplified Molecular Topology to Generate Easily Optimized Values
Journal of Chemical Information and Modeling, 2006
This paper describes a generalized method to establish the values of the five solvation parameters of solutes, which reflect, together with the five solvation parameters of solvents, the intermolecular forces involved in solutions and in some biological phenomena. The tool applied for this purpose is a simplified molecular topology (SMT), which principally takes into account, for each atom of a molecule, its nature, the nature of its bonds, and in some cases the nature of its first neighbors. The learning material used to weight the molecular features generated by SMT are two sets of experimentally determined solvation parameters, established in a previous work (Laffort et al.