In the latest issue of J. Med. Chem., researchers from Roche in Basel have a nice analysis of intramolecular hydrogen bonds in druglike molecules. An internal hydrogen bond can intuitively confer an important property on a drug; it can make the drug more lipophilic by shielding the hydrogen bonding groups from solvent. Thus, intramolecular h-bonding has emerged as a useful strategy in improving membrane permeability.
The authors look at both the CSD and the PDB and do a reasonably exhaustive analysis of HB motifs of all ligands in these two important databases. They find that internal hydrogen bonds in six membered rings are most common, followed by five and then 7 and 8 membered rings. The HBs in five membered rings are around the edge of definitions for hydrogen bond formation; this indicates the difficulty in defining a HB based on strict geometric criteria. The strongest HBs in six membered rings are, not surprisingly, those between NH and C=O groups, followed by NH and sp2 N groups. In fact nitrogen acceptors for HBs seem to be almost as common as carbonyl acceptors. The authors also find that particularly strong HBs exist for donating groups that are part of a resonance substructure such as an amide linkage (resonance assisted hydrogen bonds). Percentages of hydrogen bonded forms for various structural motifs are noted which could be useful in deliberately designing in such HBs.
After looking at various features of these HBs in several ring sizes including length, angle and torsional dependence, the authors also analyze the effects of internal HBs on membrane permeability. For this they synthesize four pairs of eight model compounds in which each pair consists of two compounds, one able to form a HB and the other one unable to (usually where the donor H is replaced with a methyl). They then calculate parameters like PAMPA permeability, logD and clogP which can be indicators of lipophilicity and permeability. They discover that because of the fragment-based rules used in calculating clogP values, computer programs cannot often predict the increase in lipophilicity resulting from internal HBs. This is a valuable finding that could be translated into a correction applied by computer programs calculating clogP.
The authors find that although internal hydrogen bonds do seem to improve logD, the relationship is not completely straightforward. The hydrogen bonding compounds can exist in closed (h-bonded) and open conformations. They find that only if the open form is a relatively low energy conformation can the molecule readily adopt the closed conformation with a hydrogen bond. They indicate how quantum chemical calculations can be useful for qualitatively rationalizing such energy differences; in one case for instance, the open form was too high in energy according to such calculations and therefore the other form was not easily populated. Because of the sharp dependence of equilibrium populations on free energy differences, I would think that the open form should not be more than about 1.8 kcal/mol higher in energy compared to the closed form (when the population of the former would be about 5%).
This overview should be useful in designing specific internal hydrogen bonds for use in drug design programs.
Kuhn, B., Mohr, P., & Stahl, M. (2010). Intramolecular Hydrogen Bonding in Medicinal Chemistry Journal of Medicinal Chemistry DOI: 10.1021/jm100087s
Shaggy parasol mushroom - but which one?
1 day ago in The Phytophactor