Free Energy Perturbation Study of Octanol/Water Partition Coefficients:  Comparison with Continuum GB/SA Calculations

Best, Scott A.; Merz, Kenneth M.; Reynolds, Charles H.

doi:10.1021/jp984215v

Cited by 99 publications

(127 citation statements)

References 107 publications

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“…40,41 Finally, the parametrization of a classical version of the GB/SA continuum model has been reported, 42 and its accuracy for predicting log P ow values has been recently summarized by comparison with free energy calculations. 31 In this study we report the parametrization of the HF/6-31G(d) version of the MST continuum model 43 for calculating free energies of solvation in n-octanol and for predicting octanol/water partition coefficients. Several reasons justify our effort.…”

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confidence: 99%

Solvation in octanol: parametrization of the continuum MST model

2001

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This study reports the parametrization of the HF/6-31G(d) version of the MST continuum model for n-octanol. Following our previous studies related to the MST parametrization for water, chloroform, and carbon tetrachloride, a detailed exploration of the definition of the solute/solvent interface has been performed. To this end, we have exploited the results obtained from free energy calculations coupled to Monte Carlo simulations, and those derived from the QM/MM analysis of solvent-induced dipoles for selected solutes. The atomic hardness parameters have been determined by fitting to the experimental free energies of solvation in octanol. The final MST model is able to reproduce the experimental free energy of solvation for 62 compounds and the octanol/water partition coefficient (log P ow ) for 75 compounds with a root-mean-square deviation of 0.6 kcal/mol and 0.4 (in units of log P), respectively. The model has been further verified by calculating the octanol/water partition coefficient for a set of 27 drugs, which were not considered in the parametrization set. A good agreement is found between predicted and experimental values of log P o/w , as noted in a root-mean-square deviation of 0.75 units of log P.

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confidence: 99%

Solvation in octanol: parametrization of the continuum MST model

2001

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“…The Gibbs free energy changes were also calculated by the continuum GB/SA models. A comparison of the results that were calculated with the FEP and GB/SA models indicated that for the set of 12 solutes in this study, GB/SA actually yielded more accurate estimates of Δlog P o/w at a significantly lower computational cost (Best et al 1999). Garrido et al computed the Gibbs free energies of solvation for several n-alkanes in 1-octanol and water using three different force fields, namely, Gromos, TraPPE, and OPLS-AA.…”

Section: Lipophilicitymentioning

confidence: 82%

In silicoADME/T modelling for rational drug design

Wang

Xing

Yue

et al. 2015

Quart. Rev. Biophys.

281

155

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Abstract. In recent decades, in silico absorption, distribution, metabolism, excretion (ADME), and toxicity (T) modelling as a tool for rational drug design has received considerable attention from pharmaceutical scientists, and various ADME/T-related prediction models have been reported. The high-throughput and low-cost nature of these models permits a more streamlined drug development process in which the identification of hits or their structural optimization can be guided based on a parallel investigation of bioavailability and safety, along with activity. However, the effectiveness of these tools is highly dependent on their capacity to cope with needs at different stages, e.g. their use in candidate selection has been limited due to their lack of the required predictability. For some events or endpoints involving more complex mechanisms, the current in silico approaches still need further improvement. In this review, we will briefly introduce the development of in silico models for some physicochemical parameters, ADME properties and toxicity evaluation, with an emphasis on the modelling approaches thereof, their application in drug discovery, and the potential merits or deficiencies of these models. Finally, the outlook for future ADME/T modelling based on big data analysis and systems sciences will be discussed.

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“…The simplicity of the potential energy function of this method makes to run very long simulations properly, in the nano and micro second time scale, and to extract valuable structural information and energy data from trajectories obtained. Other more refined molecular dynamics approaches like MD-FEP allow to calculate absolute enzyme-substrate binding free energies [37]. As a matter of fact, in all these methods it is mandatory to perform a parameterization of the ligand prior to run the molecular dynamics simulations.…”

Section: Computational Modeling Methods In Enzyme-substrate Studiesmentioning

confidence: 99%

Computational Modeling Methods for Understanding the Interaction of Lignin and Its Derivatives with Oxidoreductases as Biocatalysts

Alzate‐Morales¹,

Recabarren²,

Fuenzalida-Valdivia³

et al. 2018

Lignin - Trends and Applications

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This chapter will be presented as follow. First, a brief introduction to structure and characterization of lignin and its derivatives is presented, as well as their importance as chemical scaffolds for obtaining value-added products in chemical, food, pharmaceutical and agriculture industry. Second, an extensive review of different reports using computational modeling methods-like molecular dynamics simulations, quantum mechanics and hybrid calculation methods, among others-in the understanding of enzyme-substrate interaction and biocatalysis will be presented. Third, and as last part of chapter, some hand picked examples from literature will be chosen as successful cases where the interplay between experiment and computation has given as a result protein engineered oxidoreductases with improved catalytic capabilities.

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Free Energy Perturbation Study of Octanol/Water Partition Coefficients: Comparison with Continuum GB/SA Calculations

Cited by 99 publications

References 107 publications

Solvation in octanol: parametrization of the continuum MST model

Solvation in octanol: parametrization of the continuum MST model

In silicoADME/T modelling for rational drug design

Computational Modeling Methods for Understanding the Interaction of Lignin and Its Derivatives with Oxidoreductases as Biocatalysts

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