It is a strange phenomenon in medicinal chemistry that a measure of weight is used to assess the size of a molecule. This is akin to saying a person is 60 kg tall. This fixation on molecular weight as a measure of size gives many medicinal chemists a skewed view on the actual sizes of atoms used for drug design.
size by molecular weight
Below is a depiction of commonly used elements in drug design scaled to their respective molecular weight. Using molecular weight as a surrogate for size suggests that hydrogen is miniscule – 12 times smaller than carbon and that iodine is enormous – more than 10-times the size of carbon. This is clearly not what we were taught in school.
Medchem Atoms Scaled According to their Molecular Weight
size by heavy atom count
The second most common metric for approximating molecular size is the count of non-hydrogen atoms, also called heavy atom count. This treats all atoms as if they were the same size except for hydrogen which is ignored. This metric is much closer to the truth and should be favoured over using molecular weight. However, clearly all non-hydrogen atoms are not the same size and also hydrogen is not negligable in size or importance. In fact, hydrogen atoms are involved in almost all molecular interactions formed between a drug molecule and it’s target making it arguably the most important atom in drug design.
Medchem Atoms Scaled According to Heavy Atom Count
size by surface area
There are a number of better options for ranking atomic size: vDW radii, vDW volume or surface area. Surface area has been chosen here, as it is the surface of atoms which present themselves for non-covalent interactions. Based on surface area we see that carbon is only twice as big as hydrogen (rather than the implied 12-times based on molecular weight). The halogens chlorine, bromine and iodine in particular, suffer from the molecular weight bias. Iodine and bromine are actually only 36% and 18% larger than carbon respectively and chlorine is only marginally (6%) bigger than carbon. As screening collections often use a molecular weight cutoff they are largely devoid of chlorines, bromines and iodines despite their utility in forming halogen bonds.
McConnell’s Medchem Atoms Table
hydrogens make a difference
The size comparisons versus hydrogen and carbon in the above table are useful guides but carbon often has hydrogens attached to it which significantly increases the size of the functional group. Pauling originally assigned a value of 2.0 Å as the vDW radii for a methyl group. Probably surprising for most, this makes a methyl group the same size as an iodine atom. The size of methyl groups is further complicated by the fact that they are not spherical as halogens are. For example, the radius for methane varies between 1.897–2.504 Å (the average of which is slightly larger than Pauling´s value. Given the free rotation of methyl groups, the maximium radi of 2.5A makes a methyl group actually more sterically demanding than iodine.
van Der Waals Radii including methyl and aromatic rings
Keep the size (and not the weight) of medchem atoms in mind when you are designing drugs.
