Alkane/Water Partition Coefficient Calculation Based on the Modified AM1 Method and Internal Hydrogen Bonding Sampling Using COSMO-RS

Journal of Chemical Information and Modeling, vol. 61, pp. 3453–3462

Abstract

We introduce a physics-based model for calculating partition coefficients of solutes between water and alkanes, using a combination of a semi-empirical method for COSMO charge density calculation and statistical sampling of internal hydrogen bonds (IHBs). We validate the model on the experimental partition data (∼3500 molecules) of small organics, drug-like molecules, and statistical assessment of modeling of proteins and ligand drugs. The model combines two novel algorithms: a bond-correction method for improving the calculation of COSMO charge density from AM1 calculations and a sampling method to deal with IHBs. From a comparison of simulated and experimental partition coefficients, we find a root-mean-square deviation of roughly one log 10 unit. From IHB analysis, we know that IHBs can be present in two states: open (in water) and closed (in apolar solvent). The difference can lead to a shift of as much as two log 10 units per IHB; not taking this effect into account can lead to substantial errors. The method takes a few minutes of calculation time on a single core, per molecule. Although this is still much slower than quantitative structure-activity relationship, it is much faster than molecular simulations and can be readily incorporated into any screening method.

Authors 3

1. Panagiotis C. Petris corresponding Aachen

   Leiden University · Siemens (Netherlands)

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands

   Siemens Industry Software Netherlands B.V., Galileiweg 8, 2333 BD Leiden, The Netherlands

2. Paul Becherer

   Siemens (Netherlands)

   Affiliation as printed

   Siemens Industry Software Netherlands B.V., Galileiweg 8, 2333 BD Leiden, The Netherlands

3. J. G. E. M. Fraaije Aachen

   Leiden University · Siemens (Netherlands)

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands

   Siemens Industry Software Netherlands B.V., Galileiweg 8, 2333 BD Leiden, The Netherlands