Estimating aqueous solvation and lipophilicity of small organic molecules: A comparative overview of atom/group contribution methods

摘要

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 molecules, 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.