Lipinski’s ‘rule of 5’ includes only 4 rules: a molecular weight >500 Daltons, >5 hydrogen bond donors, >10 hydrogen bond acceptors, and a partition coefficient with a log(P) > 5. If these conditions are met, there is a reasonable chance that the small molecule drug will not work well. It may struggle to satisfy the pharmacokinetic requirements set out by ADME (absorption, distribution, metabolism, excretion).
For a successful small molecule drug, it should be a small molecule (<500 Daltons). This allows it to move through the body more freely, improving the absorption and distribution of the drug.
If a drug has more than 5 hydrogen bond donors, the molecule may struggle to be absorbed and distributed, due to interactions with other molecules (such as water and proteins). Having fewer H-bond donors may allow for more specific binding.
Having more than 10 hydrogen bond acceptors could also reduce a small molecule drug’s absorption, preventing it from efficiently being taken up.
If the partition coefficient is too high / low, the drug will not be able to be absorbed. A high partition coefficient would allow a drug to insert into the lipid bilayer of cells, but make it very challenging to remove. Contrary, a low partition coefficient would prevent a drug molecule from ever passing through the membrane. Therefore, a satisfactory balance must be found between the two extremes.
It must be stressed that not all small molecule drugs satisfy these requirements. There are exceptions to these ‘rules.’