Heuristic molecular lipophilicity potential for computer-aided rational drug design

In my thesis research, I suggest a heuristic molecular lipophilicity potential (HMLP), a structure-based technique requiring no empirical indices of atomic lipophilicity, for computer-aided drug design. 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 in calculating the electron density function ñ(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 molecules 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 HMLP gives qualitatively and quantitatively correct, as well as chemically reasonable results in cases where comparisons are available. These comparisons indicate that the HMLP has advantages over the empirical lipophilicity potential in many aspects. Three possible screening functions and parameters used in them are tested and optimized in this research. The power screening function, bi||Ri - r||ã, and the exponential screening function, biexp(-||Ri - r|| / d0), give satisfactory results. A new strategy for drug design and combinatory chemistry is presented based on HMLP, and is used in the study of a small molecular system, pyrazole and its derivatives. The mechanism of inhibition of LADH caused by pyrazole and its derivatives is explained based on the calculation results of HMLP indices. Good results are achieved in this example. Further improvements of screening function and visualization of HMLP by computer graphics are discussed. I suggest two possible visualization approaches of HMLP: a two-color system and a three-color system. Their possible applications are discussed. HMLP is suggested as a potential tool in computer-aided three-dimensional drug design, studies of 3D-QSAR, active structure of proteins, and other types of molecular interactions

Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies

The pharmacophore concept is a fundamental cornerstone in drug discovery, playing a critical role in determining the success of in silico techniques, such as virtual screening and 3D-QSAR studies. The reliability of these approaches is influenced by the quality of the physicochemical descriptors used to characterize the chemical entities. In this context, a pivotal role is exerted by lipophilicity, which is a major contribution to host-guest interaction and ligand binding affinity. Several approaches have been undertaken to account for the descriptive and predictive capabilities of lipophilicity in 3D-QSAR modeling. Recent efforts encode the use of quantum mechanical-based descriptors derived from continuum solvation models, which open novel avenues for gaining insight into structure-activity relationships studies