Grid potential analysis,virtual screening studies and ADME/T profiling on N‐arylsulfonylindoles as anti‐HIV‐1 agents

A grid potential analysis employing a novel approach of 3D quantitative structure–activity relationships (QSAR) as AutoGPA module in MOE2009.10 was performed on a dataset of 42 compounds of N‐arylsulfonylindoles as anti‐HIV‐1 agents. The uniqueness of AutoGPA module is that it automatically builds the 3D‐QSAR model on the pharmacophore‐based molecular alignment. The AutoGPA‐based 3D‐QSAR model obtained in the present study gave the cross‐validated Q² value of 0.588, r²_pred value of 0.701, r²_m statistics of 0.732 and Fisher value of 94.264. The results of 3D‐QSAR analysis indicated that hydrophobic groups at R₁ and R₂ positions and electron releasing groups at R₃ position are favourable for good activity. To find similar analogues, virtual screening on ZINC database was carried out using generated AutoGPA‐based 3D‐QSAR model and showed good prediction. In addition to those mentioned earlier, in‐silico ADME absorption, distribution, metabolism and excretion profiling and toxicity risk assessment test was performed, and results showed that majority of compounds from current dataset and newly virtually screened hits generated were within their standard limit. Copyright © 2013 John Wiley & Sons, Ltd.     

Prediction of Henry's law constant of benzene derivatives using quantum chemical continuum‐solvation models

Semiempirical (SM2, SM5.4A, MST‐AM1, COSMO‐AM1) and ab inito (HF/PCM‐vdW, MP2//PCM‐vdW, COSMO‐DFT) dielectric continuum‐solvation models as well as the surface‐tension model SM5.0R are analyzed with respect to predicting Henry's law constant at 25°C using a compound set of benzene and 39 benzene derivatives. Both hydrophilic and hydrophobic compounds are covered with a total variation in Henry's law constant of almost eight orders of magnitude corresponding to 44 kJ/mol, and the data set is selected such that there are cases where subtle changes in the molecular structure result in substantial changes of the free energy of solvation. The calculations with SM2, COSMO‐AM1, and COSMO‐DFT include solution‐phase geometry optimization, and the ab initio results refer to polarized basis sets of double‐zeta quality, with two gradient‐corrected functionals (BPW and BLYP) being used for the DFT‐based models. The results show considerable differences in performance between the different continuum‐solvation models, and among the methods yielding solvation free energies the systematic error ranges from −0.9 kJ/mol (SM5.0R) to 12.1 kJ/mol (MP2//PCM‐vdW). In particular, the nonelectrostatic solvation energy contributions of SM2, SM5.4A, MST‐AM1, and PCM‐vdW do not correlate with each other, and with PCM‐vdW omission of the nonelectrostatic component significantly improves the relative trend. The best statistics after scaling through linear regression are achieved with the electrostatic component of MP2//PCM‐vdW (r=0.94) and with COSMO‐DFT (r=0.93). The discussion includes detailed analyses of pecularities associated with certain functional groups, deviations from the expected relationship between dipole moment and solvation energy, and a simple approach to model dispersion interaction and cavitation energy by surface area terms that differentiate between individual atom types. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 17–34, 2000     

Solvation in octanol: parametrization of the continuum MST model

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. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1180–1193, 2001     

Parameterization of the Hamiltonian Dielectric Solvent (HADES) Reaction‐Field Method for the Solvation Free Energies of Amino Acid Side‐Chain Analogs

Optimization of the Hamiltonian dielectric solvent (HADES) method for biomolecular simulations in a dielectric continuum is presented with the goal of calculating accurate absolute solvation free energies while retaining the model’s accuracy in predicting conformational free‐energy differences. The solvation free energies of neutral and polar amino acid side‐chain analogs calculated by using HADES, which may optionally include nonpolar contributions, were optimized against experimental data to reach a chemical accuracy of about 0.5 kcal mol^?1. The new parameters were evaluated for charged side‐chain analogs. The HADES results were compared with explicit‐solvent, generalized Born, Poisson–Boltzmann, and QM‐based methods. The potentials of mean force (PMFs) between pairs of side‐chain analogs obtained by using HADES and explicit‐solvent simulations were used to evaluate the effects of the improved parameters optimized for solvation free energies on intermolecular potentials.     

Fragment‐based quantum mechanical calculation of protein–protein binding affinities

The electrostatically embedded generalized molecular fractionation with conjugate caps (EE‐GMFCC) method has been successfully utilized for efficient linear‐scaling quantum mechanical (QM) calculation of protein energies. In this work, we applied the EE‐GMFCC method for calculation of binding affinity of Endonuclease colicin–immunity protein complex. The binding free energy changes between the wild‐type and mutants of the complex calculated by EE‐GMFCC are in good agreement with experimental results. The correlation coefficient (R) between the predicted binding energy changes and experimental values is 0.906 at the B3LYP/6‐31G*‐D level, based on the snapshot whose binding affinity is closest to the average result from the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculation. The inclusion of the QM effects is important for accurate prediction of protein–protein binding affinities. Moreover, the self‐consistent calculation of PB solvation energy is required for accurate calculations of protein–protein binding free energies. This study demonstrates that the EE‐GMFCC method is capable of providing reliable prediction of relative binding affinities for protein–protein complexes. © 2018 Wiley Periodicals, Inc.     

Impact of the solvent on the conformational isomerism of calix[4]arenes: a study based on continuum solvation models

The influence of solvation on the conformational isomerism of calix[4]arene and p-tert-butylcalix[4]arene has been investigated by using the continuum model reported by Miertus, Scrocco, and Tomasi (MST). The quantum mechanical (QM) and semiclassical (SC) formalisms of the MST model have been considered for two different solvents (chloroform and water). The suitability of the QM-MST and SC-MST methods has been examined by comparison with previous results derived from classical molecular dynamics (MD) simulations with explicit solvent molecules. The application of the continuum model to the solute configurations generated by using in vacuo classical MD simulations provides a fast strategy to evaluate the effects of the solvent on the conformational preferences of calixarenes. These encouraging results allow us to propose the use of continuum models to solutes with complex molecular structures, which are traditionally studied by MD simulations.     

QuanPol: A full spectrum and seamless QM/MM program

The quantum chemistry polarizable force field program (QuanPol) is implemented to perform combined quantum mechanical and molecular mechanical (QM/MM) calculations with induced dipole polarizable force fields and induced surface charge continuum solvation models. The QM methods include Hartree–Fock method, density functional theory method (DFT), generalized valence bond theory method, multiconfiguration self‐consistent field method, Møller–Plesset perturbation theory method, and time‐dependent DFT method. The induced dipoles of the MM atoms and the induced surface charges of the continuum solvation model are self‐consistently and variationally determined together with the QM wavefunction. The MM force field methods can be user specified, or a standard force field such as MMFF94, Chemistry at Harvard Molecular Mechanics (CHARMM), Assisted Model Building with Energy Refinement (AMBER), and Optimized Potentials for Liquid Simulations‐All Atom (OPLS‐AA). Analytic gradients for all of these methods are implemented so geometry optimization and molecular dynamics (MD) simulation can be performed. MD free energy perturbation and umbrella sampling methods are also implemented. © 2013 Wiley Periodicals, Inc.     

Solvation enthalpies of neutral solutes in water and octanol

The balance between electrostatic and non-electrostatic enthalpic contributions to the free energy of solvation of a series of neutral solutes in water and n-octanol is examined by means of continuum solvation calculations based on the Miertus–Scrocco–Tomasi (MST) method. The experimental data indicate that the solvation enthalpy of hydrocarbons is very similar in water and n-octanol, and that the enthalpic contribution measured for polar compounds is larger in water than in n-octanol. According to MST calculations, the different magnitude of the solvation enthalpy found for polar compounds in the two solvents can be largely attributed to the electrostatic contribution. Moreover, the results point out that there is close resemblance between the non-electrostatic components for both hydrocarbons and polar compounds in the two solvents. Finally, the results show the power of current continuum models like MST to dissect the total free energy of solvation in entropic and enthalpic contributions and suggest that new refinements of continuum solvation models should include not only the fitting to solvation free energies, but also their enthalpic components.