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

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.