A statistical analysis of strong and weak hydrogen bonds in the minor groove of DNA was carried out for a set of 70 drug–DNA complexes. The terms `strong’ and `weak’ pertain to the inherent strengths and weakness of the donor and acceptor fragments rather than to any energy considerations. The dataset was extracted from the protein data bank (PDB). The analysis was performed with an in-house software, hydrogen bond analysis tool (HBAT). In addition to strong hydrogen bonds such as O−H···O and N−H···O, the ubiquitous presence of weak hydrogen bonds such as C−H···O is implicated in molecular recognition. On an average, there are 1.4 weak hydrogen bonds for every strong hydrogen bond. For both categories of interaction, the N(3) of purine and the O(2) of pyrimidine are favoured acceptors. Donor multifurcation is common with the donors generally present in the drug molecules, and shared by hydrogen bond acceptors in the minor groove. Bifurcation and trifurcation are most commonly observed. The metrics for strong hydrogen bonds are consistent with established trends. The geometries are variable for weak hydrogen bonds. A database of recognition geometries for 26 literature amidinium-based inhibitors of Human African Trypanosomes (HAT) was generated with a docking study using seven inhibitors which occur in published crystal structures included in the list of 70 complexes mentioned above, and 19 inhibitors for which the drug–DNA complex crystal structures are unknown. The virtual geometries so generated correlate well with published activities for these 26 inhibitors, justifying our assumption that strong and weak hydrogen bonds are optimized in the active site.
Volume 45, 2020
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