Uzoh, OG;
Galek, P;
Price, SL;
(2015)
Analysis of the conformational profiles of fenamates shows route towards novel, higher accuracy, force-fields for pharmaceuticals.
Physical Chemistry Chemical Physics
, 17
pp. 7936-7948.
10.1039/c4cp05525j.
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Abstract
In traditional molecular mechanics force fields, intramolecular non-bonded interactions are modelled as intermolecular interactions, and the form of the torsion potential is based on the conformational profiles of small organic molecules. We investigate how a separate model for the intramolecular forces in pharmaceuticals could be more realistic by analysing the low barrier to rotation of the phenyl ring in the fenamates (substituted N-phenyl-aminobenzoic acids), that results in a wide range of observed angles in the numerous fenamate crystal structures. Although the conformational energy changes by significantly less than 10 kJmol-1 for a complete rotation of the phenyl ring for fenamic acid, the barrier is only small because of small correlated changes in the other bond and torsion angles. The maxima for conformations where the two aromatic rings approach coplanarity arise from steric repulsion, but the maxima when the two rings are approximately perpendicular arise from a combination of an electronic effect and intramolecular dispersion. Representing the ab initio conformational energy profiles as a cosine series alone is ineffective; however, combining a cos2ξ term to represent the electronic barrier with an intramolecular atom-atom exp-6 term for all atom pairs separated by three or more bonds (1-4 interactions) provides a very effective representation. Thus we propose a new, physically motivated, generic analytical model of conformational energy, which could be combined with an intermolecular model to form more accurate force-fields for modelling the condensed phases of pharmaceutical-like organic molecules.
| Type: | Article |
|---|---|
| Title: | Analysis of the conformational profiles of fenamates shows route towards novel, higher accuracy, force-fields for pharmaceuticals |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1039/c4cp05525j |
| Publisher version: | http://dx.doi.org/10.1039/c4cp05525j |
| Language: | English |
| Additional information: | This journal is ©the Owner Societies 2015. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1462715 |
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