MOLECULAR-SIZE BASED APPROACH TO ESTIMATE PARTITION PROPERTIES FOR ORGANIC SOLUTES

A model is presented that achieves a remarkable reduction in the numbe r of parameters used to predict the log octanol-water partition coeffi cient (log P) by using a three-dimensional estimate of molecular size. An algorithm combining analytical and numerical techniques is used to compute van der Waals molecular volume and surface area. Using this c omputed volume, a simple equation that adequately describes log P for a wide variety of organic compounds is obtained by introducing only on e additional parameter. Its value is determined by the oxygen- or nitr ogen-containing functional groups present in the molecule and correlat es with hydrogen bond acceptor basicity. The corresponding free energy change agrees well with that accepted for hydrogen bonding in water. Tested on over 700 organic compounds comprising various pharmaceutical ly useful molecules, including even neutral peptides, this distinctive ly simple and fully computerized 3D approach compares favorably with e mpirical, complicated, ''two-dimensional'' fragment methods. The fact that here only a Fiery Limited number of parameters are used proves th at these 2D fragment methods were acceptable only when computation of spatial molecular structures was computationally too demanding.