Benchmark of different charges for prediction of the partitioning coefficient through the hydrophilic/lipophilic index

Abstract

A few different theoretical methods for assigning the partial atomic charges were benchmarked for calculation of the hydrophilic/lipophilic index (HLI). The coefficients were selected to produce the best correlation of the HLI values with the experimental octanol-water partition. Different parameters were checked in calculations of partial charges to get the best performance of the HLI values obtained. Thus, four partitioning schemes (Coulson, Mulliken, Merz-Kollman, Ford-Wang) were benchmarked for calculations of atomic charges with six semiempirical methods (AM1, PM3, RM1, PM6, PM6-D3H4, PM7). Moreover, five distinct types of partial atomic charges (Mulliken, Hirshfeld, Löwdin, CHELPG, NPA), obtained at the Hartree-Fock and DFT levels of theory with three basis sets, were tested for their ability to produce the HLI values with the best correlation to experimental logP coefficients of 50 mono-charged organic anions. In the case of the semiempirical methods, the best correlation between the HLI and logP values (the correlation coefficient r = 0.9216) was obtained with the AM1 Ford-Wang parametric electrostatic potential charges. The Mulliken and Coulson charges calculated with the PM7 method can be used as an alternative to AM1, with the r values of 0.9107 and 0.8984, respectively. In the case of the DFT, the PBE/def2-TZVP natural population analysis charges produce the best correlation (r = 0.9220). Nevertheless, in spite of a marginally lower performance (r = 0.9159), the NPA charges computed at the PBE/def2-SVP level are more robust and can be regarded as the optimum choice for calculating the HLI values. Graphical abstract The hydrophilic/lipophilic index (HLI).

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

“…Examples of the usage of RM1 together with other quantum chemical methods include: calculations of the enthalpy of formation of tensile cyclic molecules in condensed phase by employing electrostatic potentials and QSPR; 307 calculations of the linear free energy studies of the rates of reductive defluorination of a set of perfluorinated alkyl compounds; 301 a conformational investigation of the oxime compounds toxogonine, trimedoxime bromide (TMB-4) and obidoxime (HI-6); 341 energy and structural properties of the acid-catalyzed aromatic epoxide ring openings; 344 a benchmark computational study of the proton transfer reaction cysteine-histidine in protein environment; 325 a QM/MM evaluation of the chemical glycobiology; 318 a study of the chemical reactivity in a virtual environment; 317 a benchmark investigation of the geometries of the ground-state of p-type semiconducting molecules that exhibit different polarities; 316 evaluation of the electrostatic potentials on the docking precision of cyclin-dependent kinase 2 protein; 315 and a benchmark study in order to investigate aspects of the reaction to protonate glycine by an ion-molecule collision. 345 RM1 was also used in many studies to predict physicochemical and optical properties, such as activity coefficients, 346 reaction energies, 310,343 energy profiles of reactions, 317,329 and cysteine-histidine proton transfer reactions in different environments. 91,309,316,318,323,344 In most of these studies, RM1 was used to obtain the ground state geometries and other molecular properties, either in gas phase, or in solution (using any solvation model).…”

“…They stated: "It was concluded that RM1 methodology better agrees with γ experimental results for TPA oligomers". Another recent benchmark investigation was carried out by Fizer et al 346 that evaluated different charges in order to predict partitioning coefficient through the hydrophilic/lipophilic index. The authors concluded that: "The performance order of suitable semiempirical methods is the same as for the semiempirical Mulliken charges: PM7 > RM1 > PM6-D3H4 ≥ PM6 > PM3".…”

“…The authors concluded that: "The performance order of suitable semiempirical methods is the same as for the semiempirical Mulliken charges: PM7 > RM1 > PM6-D3H4 ≥ PM6 > PM3". 346 On the other hand, Miriyala and Řezáč 347 carried out a comparative study in order to evaluate a set of 13 semiempirical and eight density functional methods to describe the interaction energies associated with the repulsive contacts in organic molecules. The authors evaluated 160 complexes that were generated by combining 12 monomers (CO, H 2 , N 2 , acetylene, ammonia, benzene, ethylene, formaldehyde, methane, methanol, pyridine and water).…”

Molecular Partition Coefficient from Machine Learning with Polarization and Entropy Embedded Atom- Centered Symmetry Functions

“…9 It was demonstrated that entropy may contribute to significant changes in the solubility of the nanocrystalligands complexes. 10,11 In addition, in the polar phase, the solute polarizability 12 and polarity 13 are much more sensitive to the partition coefficient. The delicate balance between the entropy and the polarity in transporting small drug from phase of water to lipid was also revealed by our molecular dynamics (MD) simulations with both implicit and explicit polarization models .…”

Structure of Salicilic Hydrazone of 2-(5-Amіno-4-Phenyl-1,2,4-Triazol-3-Іlsulfanil)acetohydrazide

“…Метою даного дослідження було провести детальний аналіз структурних особливостей продукту реакції. Цей вибір обумовлений нашими попередніми дослідженнями, де було встановлено, що РМ7 добре моделює геометрію азольних систем [10,11], та є надзвичайно корисним для дослідження реакційної здатності [12] та коефіцієнту розподілу logP [13].…”