Extension of the MST continuum solvation model to the RM1 semiempirical hamiltonian

Forti, Flavio; Barril, Xavier; Luque, F. Javier; Orozco, Modesto

doi:10.1002/jcc.20814

Cited by 20 publications

(28 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The major drawback of the approach is its computational cost, which renders it unsuitable for high-throughput applications. Nevertheless, the method can be used to generate a benchmark set to test, and perhaps train, faster energy functions such as our recently implemented RM1 MST solvation model, 36 corrected semiempirical methods, 37 and others. Considering that 3D virtual screening methods have to generate conformers of up to 20 kcal mol 21 to ensure that the bioactive conformation can be found, we expect that the introduction of good quality energy functions will drastically reduce the number of configurations to consider, which should bring about a major decrease in the number of false positives and, in consequence, more reliable results.…”

Section: Discussionmentioning

confidence: 99%

Toward accurate relative energy predictions of the bioactive conformation of drugs

2008

Self Cite

View full text Add to dashboard Cite

Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol(-1) of a local minimum, with penalties above 2.0 kcal mol(-1) being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery.

show abstract

Section: Discussionmentioning

confidence: 99%

Toward accurate relative energy predictions of the bioactive conformation of drugs

2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…The majority of the compounds used in our training set are structurally rigid with little or no conformational freedom, thus, no geometry change was assumed on gas-water transition, in line with standard procedures. [85][86][87] The complete list of the training compounds, along with the computed and experimental hydration free energies is presented in Table S1 of the Supporting Information, together with the description of the optimization protocol, and the optimized parameters (cf. Table S2).…”

Section: The Mm/qm-cosmo Methodsmentioning

confidence: 99%

Quantum mechanical binding free energy calculation for phosphopeptide inhibitors of the Lck SH2 domain

Anisimov

Cavasotto

2011

J Comput Chem

View full text Add to dashboard Cite

The accurate and efficient calculation of binding free energies is essential in computational biophysics. We present a linear-scaling quantum mechanical (QM)-based end-point method termed MM/QM-COSMO to calculate binding free energies in biomolecular systems, with an improved description of entropic changes. Molecular dynamics trajectories are re-evaluated using a semiempirical Hamiltonian and a continuum solvent model; translational and rotational entropies are calculated using configurational integrals, and internal entropy is calculated using the harmonic oscillator approximation. As an application, we studied the binding of a series of phosphotyrosine tetrapeptides to the human Lck SH2 domain, a key component in intracellular signal transduction, modulation of which can have therapeutic relevance in the treatment of cancer, osteoporosis, and autoimmune diseases. Calculations with molecular mechanics Poisson-Boltzmann, and generalized Born surface area methods showed large discrepancies with experimental data stemming from the enthalpic component, in agreement with an earlier report. The empirical force field-based solvent interaction energy scoring function yielded improved results, with average unsigned error of 3.6 kcal/mol, and a better ligand ranking. The MM/QM-COSMO method exhibited the best agreement both for absolute (average unsigned error = 0.7 kcal/mol) and relative binding free energy calculations. These results show the feasibility and promise of a full QM-based end-point method with an adequate balance of accuracy and computational efficiency.

show abstract

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Although these solvation methods for uncharged molecules experienced notable advances in the last years, for charged species the models implicitly assume that no ion-pairing occurs and neglect the direct effects of counter ions and of other species in the liquid media. However, in the field of polyoxometalates (POMs), experiments demonstrate the dramatic influence of the environment on the electronic properties of POMs in solution.…”

Section: Introductionmentioning

confidence: 99%

Towards a computational treatment of polyoxometalates in solution using QM methods and explicit solvent molecules

et al. 2009

View full text Add to dashboard Cite

This study is aimed at developing an explicit solvent model for highly charged species such as polyoxometalates. The model includes solvent molecules in the first solvation shell explicitly, and long-range bulk effects and counterions as a set of single point charges. The model strongly stabilizes the electronic structure of the Keggin anion. The energies of the Kohn-Sham orbitals obtained using our model lie very close to those computed using the COSMO continuum solvent model; moreover, the total solvation energy evaluated with our model compares well to the value calculated by COSMO.

show abstract

Extension of the MST continuum solvation model to the RM1 semiempirical hamiltonian

Cited by 20 publications

References 61 publications

Toward accurate relative energy predictions of the bioactive conformation of drugs

Toward accurate relative energy predictions of the bioactive conformation of drugs

Quantum mechanical binding free energy calculation for phosphopeptide inhibitors of the Lck SH2 domain

Towards a computational treatment of polyoxometalates in solution using QM methods and explicit solvent molecules

Contact Info

Product

Resources

About