Hydrogen Bond, Hydrophobic, and Electrostatic Interactions

The predicted binding pose generated by a docking calculation is conventionally analysed in terms of the specific non-covalent interactions formed between...

The predicted binding pose generated by a docking calculation is conventionally analysed in terms of the specific non-covalent interactions formed between ligand and target, since these individual interactions provide the chemically interpretable rationale that guides subsequent medicinal chemistry design. Hydrogen bonds, formed between a donor (typically an N–H or O–H group) and an acceptor (typically a carbonyl oxygen or a basic nitrogen) at an appropriate distance and geometry, are frequently the strongest and most specificity-conferring interactions within a binding site, and their presence or absence in a predicted pose is closely scrutinised. Hydrophobic interactions, arising from the favourable burial of non-polar molecular surface within a non-polar binding pocket region, contribute substantially to overall binding affinity, particularly for larger, more lipophilic binding sites. Electrostatic interactions, including both formal salt bridges between oppositely charged groups and weaker dipole–dipole interactions, contribute additional binding specificity and are of particular importance for targets bearing a charged catalytic or binding residue. A chemically coherent, well-validated docking pose should typically demonstrate a plausible combination of all three interaction types consistent with the physicochemical character of the binding site.