Development and test of highly accurate endpoint free energy methods. 2: Prediction of logarithm of n‐octanol–water partition coefficient (logP) for druglike molecules using MM‐PBSA method

Abstract

The logarithm of n-octanol-water partition coefficient (logP) is frequently used as an indicator of lipophilicity in drug discovery, which has substantial impacts on the absorption, distribution, metabolism, excretion, and toxicity of a drug candidate. Considering that the experimental measurement of the property is costly and time-consuming, it is of great importance to develop reliable prediction models for logP. In this study, we developed a transfer free energy-based logP prediction model-FElogP.FElogP is based on the simple principle that logP is determined by the free energy change of transferring a molecule from water to n-octanol. The underlying physical method to calculate transfer free energy is the molecular mechanics-Poisson Boltzmann surface area (MM-PBSA), thus this method is named as free energy-based logP (FElogP). The superiority of FElogP model was validated by a large set of 707 structurally diverse molecules in the ZINC database for which the measurement was of high quality. Encouragingly, FElogP outperformed several commonly-used QSPR or machine learning-based logP models, as well as some continuum solvation modelbased methods. The root-mean-square error (RMSE) and Pearson correlation coefficient (R) between the predicted and measured values are 0.91 log units and 0.71, respectively, while the runner-up, the logP model implemented in OpenBabel had an RMSE of 1.13 log units and R of 0.67. Given the fact that FElogP was not parameterized against experimental logP directly, its excellent performance is likely to be expanded to arbitrary organic molecules covered by the general AMBER force fields.

Development and test of highly accurate endpoint free energy methods. 3: partition coefficient prediction using a Poisson–Boltzmann method combined with a solvent accessible surface area model for SAMPL challenges

“…The same PB radius parameters derived using HFEs in our previous work 6,7 are directly applied in toluene and cyclohexane; therefore, the only parameters of toluene and cyclohexane that differ from those of water are g and b in eqn (4) in addition to the dielectric constant. The parameterization of g and b can be obtained directly by linear regression analysis (single data point per solute), but given the limited amount of data in organic solvents, we used the multi-conformation approach to conduct the linear regression process (multiple data points per solute).…”

“…The final HFE and SFE were then derived from the arithmetic average of the three independent TI runs, while the standard deviation of the three independent runs was calculated to measure the precision of the protocol. The corresponding log P was calculated from HFE and SFE using eqn (1), and the log D was calculated from log P using eqn ( 6) and (7).…”

“…Unfortunately, it is necessary to use the same set of conformations for the solvation free energy calculation in two different solvents to achieve the best error cancellation. 31 Since the TI method demonstrates high accuracy in free energy calculations, we also employed the TI method to calculate the log P toluene/water for the 16 molecules in the SAMPL9 Fig. 4 Experimental transfer free energy versus calculated transfer free energy using the TI method for 16 drug molecules in the SAMPL9 challenge.…”

“…5 Modeling the solvent effect as a whole may lead to overfitting and the unbalanced contributions of the two types of solvent effect. Therefore, recently we conducted a series of studies on the development of a highly accurate PBSA model for SFE prediction, 6,7 which is combined with the general AMBER force field 2 (GAFF2) and our recently developed ABCG2 charge model. 8 In this new PBSA model, we developed a set of atom radii for PB calculations targeting the electrostatic (polar) contribution from the thermodynamic integration (TI) Paper PCCP calculations of hydration free energy (HFE); then the nonelectrostatic (non-polar part) term was fitted targeting the experimental values of HFE or SFE.…”

“…6 Extending this method to the solvent n -octanol yielded a prediction error of RMSE = 0.91 log units on log P octanol/water calculations of 707 drug molecules in the ZINC database. 7 We called this transfer free energy-based log P method as FELogP. Note that the PB atomic radii optimized from HFE were directly utilized for SFE calculations in organic solvents; by this way only the non-polar Δ G SASA model needs to be redeveloped for individual organic solvents.…”