Characteristic Physical Properties and Structural Fragments of Marketed Oral Drugs

An increasingly competitive pharmaceutical market demands improvement in the efficiency
and probability of drug candidate discovery. Usually these new drug candidates are targeted
for oral administration, so a detailed understanding of the molecular-level properties that relate
to optimal pharmacokinetics is a critical step toward improving the probability of selecting
successful clinical candidates. Although the characteristics of druglike molecules have been
previously discussed in the literature, the importance of this topic sustains a continued interest
for additional perspective and further detailed statistical analyses. In this contribution, we
approach the analysis from the perspective of profiling distinguishing features of orally
administered drugs. We have compiled both structural and route-administration information
for a total of 1729 marketed drugs to provide a solid basis for developing a new perspective on
the characteristics of over 1000 orally administered drugs. The molecular properties and most
commonly occurring structural elements are statistically analyzed to capture the differences
between routes of administration, as well as between marketed drugs and SAR or clinical
compounds. We find that, with respect to other routes of administration, oral drugs tend to be
lighter and have fewer H-bond donors, acceptors, and rotatable bonds than drugs with other
routes of administration. These differences are particularly pronounced when comparing the
mean values for oral vs injectable drugs. We also demonstrate that the mean property values
for oral drugs do not vary substantially with respect to launch date, suggesting that the range
of acceptable oral properties is independent of synthetic complexity or targeted receptor. Finally,
we note that, while these properties are descriptive of each class, they are not necessarily
predictive of what class any particular drug will reside in, since there is significant overlap in
the acceptable ranges found for each drug class.