Desolvation plays a very important role, particularly with ionised or polar functional groups where there will be a large unfavourable desolvation term, in addition entropic changes can also have a significant influence.Ī detailed analysis of the molecular interactions present found between ligands and macromolecules has been undertaken, "A systematic analysis of atomic protein–ligand interactions in the PDB" DOI looking at over 11,000 complexes the authors were able to categorise the 7 most common types of interaction Fig 1. With many of these interactions simply looking at a model of a protein with a ligand docked can be misleading, only considering the bound state only gives part of the equation. Hence a small steric clash can cause the loss of all affinity. However it is important to note that steric clashes can have a much more pronounced impact on affinity, the interaction between two atoms is described by the Lennard-Jones potential shown graphically below.Īs you can see the attractive forces predominate when the atoms are further apart but when they get too close the repulsive forces become dramatically dominant. Since dG=-2.303RTlogK we can calculate that a single ionic interaction might afford a 25-fold increase in affinity, whilst a hydrogen bond yield a 6-fold increase, 3.5-fold increase in binding constant for a methyl group. Other have tried to estimate the strength of interaction by using chemical double mutants. Andrews has tried to estimate the average strength of various molecular interactions by examining the structural components and binding affinities of 200 compounds. Whilst the strength of a covalent single bond is usually in the region 80-100 Kcal/mol the non-covalent interactions exploited by medicinal chemists are much weaker. Whilst the overall physicochemical properties of the molecule can have a major influence it likely that specificity might be driven by optimisation of strength and geometry of specific molecular interactions. Much of medicinal chemistry is based on the optimisation or reduction of interactions between a small molecule and a variety of biomolecules, this can be increasing the affinity of a ligand for a receptor or reducing affinity for some undesired off-target interaction such as HERG or CYP450.
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