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The partition coefficients of drug and drug-like molecules between an aqueous and organic phase are an important property for developing new therapeutics. The predictive power of computational methods is used extensively to predict partition coefficients of molecules. The application of quantum chemical calculations is used to develop methods to develop structure–activity relationship models for such prediction, either based on molecular fragment methods, or via direct calculation of solvation free energy in solvent continuum. The applicability, merits, and shortcomings of these developments are revisited here. [ABSTRACT FROM AUTHOR]

The three-dimensional reference interaction site model of the molecular solvation theory with the Kovalenko–Hirata closure is used to calculate the free energy of solvation of organic solutes in liquid aliphatic ketones. The ketone solvent sites were modeled using a modified united-atom force field. The successful application of these solvation models in calculating ketone–water partition coefficients of a large number of solutes supports the validation and benchmarking reported here. [ABSTRACT FROM AUTHOR]

The molecular solvation theory in the form of the Three-Dimensional Reference Interaction Site Model (3D-RISM) with Kovalenko–Hirata (KH) closure relation is benchmarked for use with dimethyl sulfoxide (DMSO) as solvent for (bio)-chemical simulation within the framework of integral equation formalism. Several force field parameters have been tested to correctly reproduce solvation free energy in DMSO, ion solvation in DMSO, and DMSO coordination prediction. Our findings establish a united atom (UA) type parameterization as the best model of DMSO for use in 3D-RISM-KH theory based calculations. [ABSTRACT FROM AUTHOR]

Misfolded Cu/Zn superoxide dismutase enzyme (SOD1) shows prion-like propagation in neuronal cells leading to neurotoxic aggregates that are implicated in amyotrophic lateral sclerosis (ALS). Tryptophan-32 (W32) in SOD1 is part of a potential site for templated conversion of wild type SOD1. This W32 binding site is located on a convex, solvent exposed surface of the SOD1 suggesting that hydration effects can play an important role in ligand recognition and binding. A recent X-ray crystal structure has revealed that 5-Fluorouridine (5-FUrd) binds at the W32 binding site and can act as a pharmacophore scaffold for the development of anti-ALS drugs. In this study, a new protocol is developed to account for structural (non-displaceable) water molecules in docking simulations and successfully applied to predict the correct docked conformation binding modes of 5-FUrd at the W32 binding site. The docked configuration is within 0.58 Å (RMSD) of the observed configuration. The docking protocol involved calculating a hydration structure around SOD1 using molecular theory of solvation (3D-RISM-KH, 3D-Reference Interaction Site Model-Kovalenko-Hirata) whereby, non-displaceable water molecules are identified for docking simulations. This protocol was also used to analyze the hydrated structure of the W32 binding site and to explain the role of solvation in ligand recognition and binding to SOD1. Structural water molecules mediate hydrogen bonds between 5-FUrd and the receptor, and create an environment favoring optimal placement of 5-FUrd in the W32 binding site. [ABSTRACT FROM AUTHOR]

The state-of-the-art molecular solvation theory is used to predict skin permeability of a large set of compounds with available experimental skin permeability coefficient (logKP). Encouraging results are obtained pointing to applicability of a novel quantitative structure activity model that uses statistical physics based 3D-RISM-KH theory for solvation free energy calculations as a primary descriptor for the prediction of logKP with relative mean square error of 0.77 units. [ABSTRACT FROM AUTHOR]

Molecular theory of solvation, a.k.a., three-dimensional reference interaction site model theory of solvation with Kovalenko–Hirata closure relation (3D-RISM-KH), is an accurate and fast theory predicting solvation free energy and structure. Here we report a benchmark study of n-octanol solvation free energy calculations using this theory. The choice of correct force field parameters is quintessential for the success of 3D-RISM theory, and we present a guideline to obtain them for n-octanol solvent. Our best prediction of the solvation free energy on a set of 205 small organic molecules supplemented with the so-called "universal correction" scheme yields relative mean unsigned error of 0.94 kcal/mol against the reported database. The best agreement is obtained with the united atom (UA) type force field parametrization of n-octanol with the van der Waals parameters of hydroxyl hydrogen reported by Kobryn et al. [Kobryn, A. E.; Kovalenko, A. J. Chem. Phys. 2008, 129, 134701]. [ABSTRACT FROM AUTHOR]

• Liquid alkane solvation models were optimized for 3D-RISM applications. • Liquid structures were compared between 3D-RISM-KH and DFT-D3 computations. • Solvation free energy calibrations for 3D-RISM-KH were done using a universal correction type scheme. • Alkane-water partition coefficients of organic compounds were calculated via the 3D-RISM-KH theory. The performance of the 3D-reference interaction site model (3D-RISM) with the Kovalenko-Hirata (KH) closure is benchmarked for liquid alkanes. The liquids are modelled using the united atom formalism. The intermolecular distribution functions obtained from the computations are in good agreement with the experimental reports. The solvation free energy (SFE) computed in the alkanes for a large set of solutes also agrees well with the experimental data. The molecular partition coefficients for alkane-water partition of the compounds were calculated for cyclohexane-water, alkane-water, and hexadecane-water partitions of a total of eight hundred and forty-three organic compounds with reliable accuracy. A calibration scale is proposed for alkane-water partition coefficient calculations based on the 3D-RISM-KH theory. [ABSTRACT FROM AUTHOR]

[Display omitted] • Liquid straight chain aliphatic carboxylic acids were studied with various computational methods. • Ordered multimeric structures were found to exist in the bulk liquids for liquid acids. • All-atom MD and united atom RISM calculations provided comparable distributions of solvent sites. • Hydrated forms of the acetic acid and perhalo acetic acids were explored. • Density functional theory calculations provide structural insights of the neat and hydrated acid clusters. The liquid structures of short straight chain aliphatic carboxylic acids (C1-C6) and halogenated acetic acids (trifluoro and trichloro) are analyzed with molecular dynamics simulations, three-dimensional reference interaction site model, and density functional theory calculations. The neat acids are found to exist in multimeric ordered form consisting of both open chain and cyclic oligomers. Introduction of water breaks the hydrogen bonding networks between adjacent acetic acid molecules by inserting water as a bridging molecule. The electronic structure calculations confirm the formation of chain and ring type structures in the liquid state. [ABSTRACT FROM AUTHOR]

[Display omitted] • The 3D Reference Interaction Site Model is used to explore liquid oleyl alcohol. • The 3D-RISM simulations produced the liquid oleyl alcohol structure qualitatively similar to the MD simulation. • The united atom TRAPPE force field is used for bulk susceptibility calculation of the liquid. • The molecular partitioning in alcohol/water media is calculated with RMSD of 0.48 unit. • A new QSAR model is presented for the partition function calculation. The 3D-RISM-KH molecular solvation theory is applied to liquid long chain unsaturated oleyl alcohol to explore the structure of the liquid and to calculate alcohol/water partition coefficients. The united atom TraPPE force field parameters resulted in comparable structural information between RISM and MD simulations. The RISM theory and the MD simulation point to a relatively ordered liquid structure of oleyl alcohol. The molecular partition coefficients were computed with a root mean square deviation of 0.48 unit via a predictive quantitative structure activity relationship. [ABSTRACT FROM AUTHOR]

The statistical mechanics-based 3-dimensional reference interaction site model with the Kovalenko-Hirata closure (3D-RISM-KH) molecular solvation theory has proven to be an essential part of a multiscale modeling framework, covering a vast region of molecular simulation techniques. The successful application ranges from the small molecule solvation energy to the bulk phase behavior of polymers, macromolecules, etc. The 3D-RISM-KH successfully predicts and explains the molecular mechanisms of self-assembly and aggregation of proteins and peptides related to neurodegeneration, protein-ligand binding, and structure-function related solvation properties. Upon coupling the 3D-RISM-KH theory with a novel multiple time-step molecular dynamic (MD) of the solute biomolecule stabilized by the optimized isokinetic Nosé–Hoover chain thermostat driven by effective solvation forces obtained from 3D-RISM-KH and extrapolated forward by generalized solvation force extrapolation (GSFE), gigantic outer time-steps up to picoseconds to accurately calculate equilibrium properties were obtained in this new quasidynamics protocol. The multiscale OIN/GSFE/3D-RISM-KH algorithm was implemented in the Amber package and well documented for fully flexible model of alanine dipeptide, miniprotein 1L2Y, and protein G in aqueous solution, with a solvent sampling rate ~150 times faster than a standard MD simulation in explicit water. Further acceleration in computation can be achieved by modifying the extent of solvation layers considered in the calculation, as well as by modifying existing closure relations. This enhanced simulation technique has proven applications in protein-ligand binding energy calculations, ligand/solvent binding site prediction, molecular solvation energy calculations, etc. Applications of the RISM-KH theory in molecular simulation are discussed in this work. [ABSTRACT FROM AUTHOR]