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

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.

Molecular modeling of the interface of an egg yolk protein-based emulsion

“…The Gibbs energy of mixing was calculated through COSMO-RS calculations, 82,83 using the charge envelope of the fragments (the so-called sigma profiles). The COSMO charge envelope is here computed via a modified version of AM1, [84][85][86] using atomic partial charges derived from the charge equilibration (QEq) method. 87 By definition the residual Gibbs energy of mixing between identical fragments is zero, i.e., ∆G res,ii = 0, thus it follows trivially that a ii is reduced only to the excluded volume contribution and, in particular, for water bead self-interaction a ww = α EV .…”

Quantitative Structure-Activity Relationship of 3-Thiocyanate-1H-Indoles Derived Compounds as Antileukemia by AM1, PM3, and RM1 Methods

“…Several QSAR studies have been conducted in the search for anticancer compounds, such as those utilizing the Austin model 1 (AM1) and parameterized model 3 (PM3) semi-empirical methods for the QSAR application of estradiol-derived compounds [5,10], as well as the PM3 method for the QSAR of calanone-derived compounds [11]. Modified AM1 has also been used for calculating alkane/water partition coefficients [12], while PM3 has been used in molecular simulations [13]. Furthermore, the RM1 (Recife Model 1) method, a method used in Monte Carlo simulation [14] and available in Hyperchem version 8, is widely used for calculating the enthalpy of formation, dipole moment, net charge, ionization potential, and structure geometry [15].…”