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 kJ mol(-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 cos 2ξ 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.
Highlights
Applying traditional force-fields to pharmaceutical-like molecules, with flexible bonds linking multiple functional groups, often relies on poorly justified transferability assumptions for lack of data for empirical fitting[14,15] and are often unsuccessful for simulating the properties of pharmaceuticals materials.167936 | Phys
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, that results in a wide range of observed angles in the numerous fenamate crystal structures
The conformational profiles used throughout this study, unless otherwise specified, were relaxed conformational energy scans at PBE0/6-31+G(d) level of theory, carried out using GAUSSIAN03.63 We found that the results of tolfenamic acid (TA) were sensitive to the atoms used to define the torsion angle, (i.e. Fig. S1 of the Electronic supplementary information (ESI)† shows that defining the torsion by H6–N1–C8–C9 or H6–N1–C8–C13 could double the height of the maximum at x = 01, and even using C7–N1–C8–C13 could show differences at high energies as x approached 1801)
Summary
Applying traditional force-fields to pharmaceutical-like molecules, with flexible bonds linking multiple functional groups, often relies on poorly justified transferability assumptions for lack of data for empirical fitting[14,15] and are often unsuccessful for simulating the properties of pharmaceuticals materials.167936 | Phys. We need to model the molecular flexibility of typical pharmaceutical molecules by a force-field that accurately reproduces the relative energies of the known and thermodynamically competitive crystal structures and yet can be evaluated sufficiently quickly for realistic Molecular Dynamics simulations. Such a force-field would be used for assessing crystal stability at ambient temperatures, calculating the relative free energies of known and potential polymorphs, and for simulating nucleation and other molecular recognition processes of the molecules.[35]
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