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

• Published in: Journal of chemical information and modeling Vol. 61; no. 7; pp. 3453 - 3462
• Main Authors: Petris, Panagiotis C, Becherer, Paul, Fraaije, Johannes G. E. M
• Format: Journal Article
• Language: English
• Published: Washington American Chemical Society 26.07.2021
• Subjects: Algorithms; Alkanes; Charge density; Coefficients; Computational Biochemistry; Empirical analysis; Hydrogen bonding; Hydrogen bonds; Mathematical models; Sampling methods
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.0c01478

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.