Atomic Physicochemical Parameters for Three-Dimensional Structure-Directed Quantitative Structure-Activity Relationships I. Partition Coefficients as a Measure of Hydrophobicity

Earlier we showed (A. K. Ghose and G. M. Crippen, J. Med. Chem., 28, 333, 1985) the necessity of atomic physicochemical parameters in three-dimensional receptor mapping. Here we derive more refined and widely applicable hydrophobicity parameters. Carbon, hydrogen, oxygen, nitrogen, sulfur, and halogens are classified into 110 atom types. Among these, the hydrophobic contributions of 90 atom types have been evaluated from the log P_{(water-octanol)} values of 494 molecules, using the additive model and leastsquares technique. It gave a standard deviation of 0.347, a correlation coefficient of 0.962, and an explained variance of 0.908. These atomic values were used to predict the log P values of 69 compounds. The predicted values showed a standard deviation of 0.404 and a correlation coefficient of 0.896. This work has been compared with more conventional approaches.     

微乳液相色谱测定药物的油-水分配系数的新方法研究

建立快速微乳液相色谱法(MELC)测定药物的油-水分配系数(log P)的方法. 选择5种模拟生物膜的微乳流动相体系, 以7个标准药物的log P对保留因子(log k)的回归线性方程, 计算被测药物的log P值. 并以药物文献的log P值对实验测得log k值的线性相关系数为参数, 对微乳体系的表面活性剂和油相的种类进行考察, 得到测定非同类的中性、碱性药物的油-水分配系数最佳流动相体系为6.0% Brij35-6.6%正丁醇-0.8%正辛醇-86.6%磷酸缓冲液(0.05 mol• L－1, pH 7.0), 其测得值与文献的实验值平均相差0.3个对数单位. 结果显示该方法可靠、高效、重现性好, 可用于药物的油-水分配系数log P的测定.     

ADME evaluation in drug discovery. 2. Prediction of partition coefficient by atom-additive approach based on atom-weighted solvent accessible surface areas

A novel method for the calculations of 1-octanol/water partition coefficient (log P) of organic molecules has been presented here. The method, SLOGP v1.0, estimates the log P values by summing the contribution of atom-weighted solvent accessible surface areas (SASA) and correction factors. Altogether 100 atom/group types were used to classify atoms with different chemical environments, and two correlation factors were used to consider the intermolecular hydrophobic interactions and intramolecular hydrogen bonds. Coefficient values for 100 atom/group and two correction factors have been derived from a training set of 1850 compounds. The parametrization procedure for different kinds of atoms was performed as follows: first, the atoms in a molecule were defined to different atom/group types based on SMARTS language, and the correction factors were determined by substructure searching; then, SASA for each atom/group type was calculated and added; finally, multivariate linear regression analysis was applied to optimize the hydrophobic parameters for different atom/group types and correction factors in order to reproduce the experimental log P. The correlation based on the training set gives a model with the correlation coefficient (r) of 0.988, the standard deviation (SD) of 0.368 log units, and the absolute unsigned mean error of 0.261. Comparison of various procedures of log P calculations for the external test set of 138 organic compounds demonstrates that our method bears very good accuracy and is comparable or even better than the fragment-based approaches. Moreover, the atom-additive approach based on SASA was compared with the simple atom-additive approach based on the number of atoms. The calculated results show that the atom-additive approach based on SASA gives better predictions than the simple atom-additive one. Due to the connection between the molecular conformation and the molecular surface areas, the atom-additive model based on SASA may be a more universal model for log P estimation especially for large molecules.     

Simulation of chromatography of phenolic compounds with a computational chemical method

An ab initio simulation of reversed-phase liquid chromatography for phenolic compounds was achieved based on molecular interaction energy values calculated using molecular mechanics calculations (MM2) of the CAChe program. The precision of the predicted retention factors from the molecular interaction energy values was equivalent to the predicted retention factors based on octanol-water partition coefficients (log P) calculated using the molecular orbital package (MOPAC). The prediction of retention factors of phenolic compounds in reversed-phase liquid chromatography in a given pH eluent was possible using the predicted dissociation constant (pKa) from the atomic partial charge without a chemical experiment if the organic modifier effect was known.     

Evaluation of a Simple HPLC Correlation Method for the Estimation of the Octanol-Water Partition Coefficients of Organic Compounds

Abstract

A simple reverse-phase high performance liquid chromatographic method is evaluated for the estimation of octanol-water partition coefficients (log P) of organic compounds by correlation with their chromatographic capacity factors (k′). Using an unmodified commercial octadecylsilane column and a mobile phase consisting of methanol and an aqueous buffer, a linear relationship is established between the literature log P values of 68 compounds and the logarithms of their k′ values. For the determination of the partition coefficients of unknowns, one of two sets of standards is used to calibrate the system, the choice being dependent on the hydrogen-bonding character of the compounds being evaluated. The overall method is shown to be rapid and widely adaptable and to give log P data which are comparable to results obtained by classical or other correlation methods.     

固相微萃取技术在估算多环芳烃的辛醇-水分配系数中的应用

采用固相微萃取 气相色谱／质谱联用技术分析了水中１１种多环芳烃,并获得其平衡时的分配系数。当固相微萃取纤维上涂渍的固定液被视为一种有机溶剂时,根据萃取系统间线性的自由能关系,建立了聚二甲基硅氧烷 水分配系数（Ｋｓｗ）与正辛醇 水分配系数（Ｋｏｗ）间的关系式,并将其应用于估算其它多环芳烃的未知的醇 水分配系数。所建立的方法简单、快速,与Ｌｅｏ碎片法相比,可以更精确地估算取代基位置不同的同分异构体的Ｋｏｗ。     

修正的分子连接性指数mL用于氯代苯、醇、酯的QSAR/QSRR研究

在分子拓扑理论的基础上，提出了1个改进的连接性指数气^mL并用气研究了氯代苯、醇、酯的正辛醇-水分配系数及气相色谱保留指数，^mL不仅对这些有机化合物有良好的结构选择性，而且与其正辛醇-水分配系数、气相色谱保留指数有良好的相关性；由方程得出的预测值与实验测定值之间能较好地吻合。     

Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning

Bioactive compounds generally need to cross membranes to arrive at their site of action. The octanol-water partition coefficient (lipophilicity, logP_OW) has proven to be an excellent proxy for membrane permeability. In modern drug discovery, logP_OW and bioactivity are optimized simultaneously, for which fluorination is one of the relevant strategies. The question arises as to which extent the often subtle logP modifications resulting from different aliphatic fluorine-motif introductions also lead to concomitant membrane permeability changes, given the difference in molecular environment between octanol and (anisotropic) membranes. It was found that for a given compound class, there is excellent correlation between logP_OW values with the corresponding membrane molar partitioning coefficients (logK_p); a study enabled by novel solid-state ¹⁹F NMR MAS methodology using lipid vesicles. Our results show that the factors that cause modulation of octanol-water partition coefficients similarly affect membrane permeability.     

Fast,efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation

We present the first global parameterization and validation of a novel charge model, called AM1-BCC, which quickly and efficiently generates high-quality atomic charges for computer simulations of organic molecules in polar media. The goal of the charge model is to produce atomic charges that emulate the HF/6-31G* electrostatic potential (ESP) of a molecule. Underlying electronic structure features, including formal charge and electron delocalization, are first captured by AM1 population charges; simple additive bond charge corrections (BCCs) are then applied to these AM1 atomic charges to produce the AM1-BCC charges. The parameterization of BCCs was carried out by fitting to the HF/6-31G* ESP of a training set of >2700 molecules. Most organic functional groups and their combinations were sampled, as well as an extensive variety of cyclic and fused bicyclic heteroaryl systems. The resulting BCC parameters allow the AM1-BCC charging scheme to handle virtually all types of organic compounds listed in The Merck Index and the NCI Database. Validation of the model was done through comparisons of hydrogen-bonded dimer energies and relative free energies of solvation using AM1-BCC charges in conjunction with the 1994 Cornell et al. forcefield for AMBER.(13) Homo- and hetero-dimer hydrogen-bond energies of a diverse set of organic molecules were reproduced to within 0.95 kcal/mol RMS deviation from the ab initio values, and for DNA dimers the energies were within 0.9 kcal/mol RMS deviation from ab initio values. The calculated relative free energies of solvation for a diverse set of monofunctional isosteres were reproduced to within 0.69 kcal/mol of experiment. In all these validation tests, AMBER with the AM1-BCC charge model maintained a correlation coefficient above 0.96. Thus, the parameters presented here for use with the AM1-BCC method present a fast, accurate, and robust alternative to HF/6-31G* ESP-fit charges for general use with the AMBER force field in computer simulations involving organic small molecules.     

Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distribution

Octanol-water partition coefficients are the most widely used measure of lipophilicity in modelling biological partition/distribution. It has long been recognised that the retention of a compound in reversed-phase liquid chromatography is governed by its lipophilicity/hydrophobicity, and thus shows correlation with an octanol-water partition coefficient. A great number of publications have reported the efforts made to adjust HPLC conditions to measure surrogate octanol-water partition coefficients. However, there is no general consensus in this field. HPLC provides a platform to measure various types of lipophilicity that can provide relevant information about the compounds' property. In this way HPLC can be more valuable than just a surrogate for octanol-water partition. Chromatography using biomimetic stationary phases may provide better insight for biological partition/distribution processes. The research in this field is still ongoing and a large variety of HPLC conditions have been suggested. This review will outline approaches to overcoming the difficulties of standardisation and describe different theoretical approaches for comparison of HPLC lipophilicity data obtained under various conditions, along with the relation of these results to biological partition/distribution.     

Extended solvent-contact model approach to SAMPL4 blind prediction challenge for hydration free energies

Extended solvent-contact model was applied to the blind prediction of the hydration free energies of 47 organic molecules included in the SAMPL4 data set. To obtain a suitable prediction tool, we constructed a hydration free energy function involving three kinds of atomic parameters. With respect to total 34 atom types introduced to describe all SAMPL4 molecules, 102 atomic parameters were defined and optimized with a standard genetic algorithm in such a way to minimize the difference between the experimental hydration free energies and those calculated with the hydration free energy function. In this parameterization, we used a training set comprising 77 organic molecules with varying sizes and shapes. The estimated hydration free energies for the SAMPL4 molecules compared reasonably well with the experimental results with the associated squared correlation coefficient and root mean square deviation of 0.89 and 1.46 kcal/mol, respectively. Based on the comparative analysis of experimental and computational hydration free energies of the SAMPL4 molecules, the methods for further improvement of the present hydration model are suggested.     

Comparison of two simulation methods to compute solvation free energies and partition coefficients

The thermodynamic integration (TI) and expanded ensemble (EE) methods are used here to calculate the hydration free energy in water, the solvation free energy in 1‐octanol, and the octanol‐water partition coefficient for a six compounds of varying functionality using the optimized potentials for liquid simulations (OPLS) all‐atom (AA) force field parameters and atomic charges. Both methods use the molecular dynamics algorithm as a primary component of the simulation protocol, and both have found wide applications in fields such as the calculation of activity coefficients, phase behavior, and partition coefficients. Both methods result in solvation free energies and 1‐octanol/water partition coefficients with average absolute deviations (AAD) from experimental data to within 4 kJ/mol and 0.5 log units, respectively. Here, we find that in simulations the OPLS‐AA force field parameters (with fixed charges) can reproduce solvation free energies of solutes in 1‐octanol with AAD of about half that for the solute hydration free energies using a extended simple point charge (SPC/E) model of water. The computational efficiency of the two simulation methods are compared based on the time (in nanoseconds) required to obtain similar standard deviations in the solvation free energies and 1‐octanol/water partition coefficients. By this analysis, the EE method is found to be a factor of nine more efficient than the TI algorithm. For both methods, solvation free energy calculations in 1‐octanol consume roughly an order of magnitude more CPU hours than the hydration free energy calculations. © 2012 Wiley Periodicals, Inc.     

A 3D QSAR pharmacophore model and quantum chemical structure--activity analysis of chloroquine(CQ)-resistance reversal

Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.     

多氯联苯的正辛醇-空气分配系数与气相色谱保留参数的关联

通过对19种多氯联苯（PCBs）在DB-1,DB-5和DB-1701等3种色谱柱上的气相色谱（GC）保留参数A,B值与正辛醇-空气分配系数(Koa)的相关分析,发现GC保留参数A,B与Koa存在明显的线性关系。采用了逐步回归的方法,建立了保留参数A,B与Koa的二元回归方程,相关系数的平方达到了0.99以上,标准偏差小于0.11。此外,根据实验测定的153个PCBs的GC保留参数以及定量构效关系（QSAR）研究中的56个预测值,对剩余190种PCBs的Koa值进行了预测。