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Issue 35, 2012
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Evaluating the enthalpic contribution to ligand binding using QM calculations: effect of methodology on geometries and interaction energies

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Abstract

As a result of research on ligand efficiency in the pharmaceutical industry, there is greater focus on optimizing the strength of polar interactions within receptors, so that the contribution of overall size and lipophilicity to binding can be decreased. A number of quantum mechanical (QM) methods involving simple probes are available to assess the H-bonding potential of different heterocycles or functional groups. However, in most receptors, multiple features are present, and these have distinct directionality, meaning very minimalist models may not be so ideal to describe the interactions. We describe how the use of gas phase QM models of kinase proteinligand complex, which can more closely mimic the polar features of the active site region, can prove useful in assessing alterations to a core template, or different substituents. We investigate some practical issues surrounding the use of QM cluster models in structure based design (SBD). These include the choice of the method; semi-empirical, density functional theory or ab-initio, the choice of the basis set, whether to include implicit or explicit solvation, whether BSSE should be included, etc. We find a combination of the M06-2X method and the 6-31G* basis set is sufficiently rapid, and accurate, for the computation of structural and energetic parameters for this system.

Graphical abstract: Evaluating the enthalpic contribution to ligand binding using QM calculations: effect of methodology on geometries and interaction energies

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Supplementary files

Publication details

The article was received on 02 Apr 2012, accepted on 27 Jun 2012 and first published on 29 Jun 2012


Article type: Paper
DOI: 10.1039/C2OB25657F
Citation: Org. Biomol. Chem., 2012,10, 7053-7061
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    Evaluating the enthalpic contribution to ligand binding using QM calculations: effect of methodology on geometries and interaction energies

    D. Gleeson, B. Tehan, M. P. Gleeson and J. Limtrakul, Org. Biomol. Chem., 2012, 10, 7053
    DOI: 10.1039/C2OB25657F

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